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Detoxifying enzyme genotypes and susceptibility to cutaneous malignancy
Abstract
While ultraviolet (UV) exposure is thought to be a major risk factor for basal cell carcinoma (BCC) and squamous cell carcinoma, more recent research has focused on genetic factors predisposing to these cancers. UV constitutes an oxidative stress with generation of free radicals, leading to lipid and DNA damage and gene mutation. It could therefore be hypothesized that individual ability to deal with these products may be important in cutaneous carcinogenesis. It is clear from recent studies that polymorphisms in detoxifying enzyme genes are important in determining susceptibility to skin cancer. The magnitude of effect in BCC is similar to that seen with many other previously described risk factors. However, uncertainties exist regarding the phenotypic consequences of some of these polymorphisms and relevant substrates. This review describes the influence of polymorphisms in detoxifying enzymes in determining susceptibility to skin cancer (in particular to BCC) and give a brief overview of the biochemistry of the detoxification process.
... Without UV exposure as a tumor initiator and promoter, it is unlikely that phenotypic factors play a part in skin carcinogenesis, but with adequate exposure they are likely to play a large part. Exposure to UV radiation is well known to cause direct damage to DNA via UVB and indirect damage to DNA via UVA-induced oxidative stress, with UVB also contributing a small amount to indirect damage (Seo et al, 1996;Lear et al, 2000). Mutations of the p53 gene, caused by UVB radiation, appear to be an early event in skin cancer as they are found in SK as well as in normal, sun-damaged skin (Ziegler et al, 1994). ...
... More importantly, UVA radiation and to a much lesser extent UVB radiation are known to cause indirect damage to DNA by induction of oxidative stress . This produces reactive oxygen species that interact with lipids, proteins, and DNA to generate intermediates that combine with DNA to form adducts (Lear et al, 2000). ...
... GSTM1 also catalyzes the conjugation of DNA hydroperoxide, a product of DNA oxidation (Kerb et al, 1997). In addition, GSTM1 is capable of catalyzing conjugation to 5-hydroxymethyluracil, a mutagenic compound that is formed by either oxidative attack on the methyl group of the thymine base of DNA or from deamination of products formed by oxidation of 5-methylcytosine (Boorstein et al, 1989;Lear et al, 2000). ...
... That's why it as been suggested that several low-penetrance susceptibility genes may alter the predisposition to cutaneous melanoma. Studies for discovery of genetic factors responsible for development of sporadic melanoma are focused principally on genes and their protein products implicated in the regulation f skin tanning, DNA reparation, detoxification of oxidative metabolites and production of immune modulatory mediators (Ichii-Jones, Lear et al. 1998; Strange, Ellison et al. 1999; Lear, Smith et al. 2000; Kanetsky, Holmes et al. 2001; Wei, Lee et al. 2003; Landi, Kanetsky et al. 2005; Dolzan, Rudolf et al. 2006; Fargnoli, Argenziano et al. 2006; Mossner, Anders et al. 2007; Bishop, Demenais et al. 2009; Schoof, von Bonin et al. 2009) Such low-penetrance susceptibility genes might be the genes encoding the detoxification of oxidative stress product, which are considered as important factors influencing the risk of cutaneous melanoma and other skin cancers associated with UV irradiation (Lear, Heagerty et al. 1996; Kerb, Brockmoller et al. 1997; Lear, Smith et al. 2000; Kanetsky, Holmes et al. 2001; Kerb, Brockmoller et al. 2002; Dolzan, Rudolf et al. 2006; Mossner, Anders et al. 2007; Povey, Darakhshan et al. 2007). GSTM1 and GSTT1 have been suggested as some of these low-penetrance susceptibility genes since they code for cytoplasmic GST-mu and GST-theta enzymes, which are involved in conjugation and in most cases detoxification with reduced glutathione of numerous electrophilic compounds with exogenic and endogenic origin including oxidative stress products (Hayes, Flanagan et al. 2005). ...
... That's why it as been suggested that several low-penetrance susceptibility genes may alter the predisposition to cutaneous melanoma. Studies for discovery of genetic factors responsible for development of sporadic melanoma are focused principally on genes and their protein products implicated in the regulation f skin tanning, DNA reparation, detoxification of oxidative metabolites and production of immune modulatory mediators (Ichii-Jones, Lear et al. 1998; Strange, Ellison et al. 1999; Lear, Smith et al. 2000; Kanetsky, Holmes et al. 2001; Wei, Lee et al. 2003; Landi, Kanetsky et al. 2005; Dolzan, Rudolf et al. 2006; Fargnoli, Argenziano et al. 2006; Mossner, Anders et al. 2007; Bishop, Demenais et al. 2009; Schoof, von Bonin et al. 2009) Such low-penetrance susceptibility genes might be the genes encoding the detoxification of oxidative stress product, which are considered as important factors influencing the risk of cutaneous melanoma and other skin cancers associated with UV irradiation (Lear, Heagerty et al. 1996; Kerb, Brockmoller et al. 1997; Lear, Smith et al. 2000; Kanetsky, Holmes et al. 2001; Kerb, Brockmoller et al. 2002; Dolzan, Rudolf et al. 2006; Mossner, Anders et al. 2007; Povey, Darakhshan et al. 2007). GSTM1 and GSTT1 have been suggested as some of these low-penetrance susceptibility genes since they code for cytoplasmic GST-mu and GST-theta enzymes, which are involved in conjugation and in most cases detoxification with reduced glutathione of numerous electrophilic compounds with exogenic and endogenic origin including oxidative stress products (Hayes, Flanagan et al. 2005). ...
Epidemiological investigations during the last decades have proven that the cutaneous malignant melanoma is a complex disease. There are variety of genetic and environmental factors and their interactions which are implicated in the developments of this neoplastic disease. The enhanced ultraviolet exposure (UV) is considered as the most important environmental factor contributing to skin melanoma. It has been fund that UV light has a pleiotropic effect on the skin cells, which includes both direct damage of DNA due to formation of pyrimidine (thymine) dimmers and indirect effect via generation of reactive oxygen species (ROS). In this respect the gene variants in enzymes involved in detoxification of the oxidative stress products are considered as important factors influencing the risk for development of cutaneous malignant melanoma and other types of skin cancers promoted by UV exposure. GSTT1 and GSTM1 are isoenzymes of the large family of glutathione-S-transferases, expressed in the skin and able to detoxify products of oxidative stress reactions caused by UV irradiation. The aim of the current study was to examine the relation of GSTM1 and GSTT1 null polymorphisms with skin malignant melanoma risk in a pilot case-control study of Bulgarian patients and unaffected controls. A modified multiplex (duplex/triplex) PCR-based method was applied for detection of GSTs' genotypes. Our results showed no statistically significant difference between melanoma patients and healthy controls in the frequency of null GSTM1 genotype (p=0.505, χ2-test). However there was a tendency for increased risk for melanoma in carriers of GSTT1 null genotype (p=0.107, χ2-test), especially among the females who appeared to have more than five time higher risk than the women with non-null GSTT1 genotype (OR=5.60, 95% CI, 1.54-20.43, p=0.014, Fisher's exact test). Our current results suggest that the inherited absence of GST-theta, but not of GST-mu detoxifying enzymes due to the presence of homozygous null genotypes may be associated with skin malignant melanoma, especially in women.
... AhR activation has been recently shown to promote carcinogenesis in the skin of mice [40]. Moreover, earlier studies have also implicated polymorphisms of the AhR-depended detoxifying enzymes, such as the CYP enzymes and glutathione-S-transferase (GST) in the pathogenesis of BCC [41,42]. Hence, we suggest that Malassezia-produced AhR ligands could act as skin carcinogens, especially for BCC. ...
... Solar UV exposure is the most important single carcinogen for BCC, yet by far not every BCC can be attributed to sun exposure, and additional factors related to the host contribute substantially to the pathogenesis of many BCC cases [23]. Among hostdependent factors that have been linked to the occurrence of multiple BCCs on the same patient are polymorphisms in detoxifying enzymes [41,42]. The aforementioned non-homogeneous, partly UVR-independent anatomical distribution of these tumors is in line with the current hypothesis that carcinogenic factors acting in loco independently or in addition to UVR, may play a distinctive role in the pathogenesis of BCC. ...
... In den letzten Jahren wurde dieses Konzept auch auf [Ponder, 1997]. Gene mit hoher Penetranz sind auch für die bekannten Genodermatosen wie die Tuberöse Sklerose, die Neurofibromatosis generalisata und die Epidermolysis bullosa verantwortlich [Moss, 1991;Christiano und Uitto, 1992] [Cox et al., 1998], die Psoriasis [Asadullah et al., 2001] und für maligne Hauttumoren [Lear et al., 2000] konnte ein solcher Zusammenhang bereits aufgezeigt werden. ...
... Hauttumoren [Lear et al., 2000] [Nakachi et al., 1991;Ichiba et al., 1994] Glutathion-S-Transferasen (GST) [Seidegard et al., 1986;Ketterer et al., 1992;Rebbeck, 1997;Bennett et al., 1999] und N-Acetyltransferasen (NAT) [Wikman et al., 2001] vorkommt. Es konnte gezeigt werden, daß Urushiol-Proteinverbindungen in vitro eine Proliferation von Lymphozyten auslösen, die zuvor bei sensibilisierten Patienten entnommen worden waren [Dupuis, 1979]. ...
Die allergische Kontaktdermatitis ist eine multifaktoriell bedingte Hauterkrankung, bei deren Entstehung sowohl Umweltfaktoren als auch individuelle Risikofaktoren beteiligt sind. Bis heute ist es aber noch nicht geklärt, warum bestimmte Individuen durch Hautkontakt mit einem Allergen eine Sensibilisierung entwickeln, während andere trotz jahrelanger Exposition verschont bleiben. Bei dem Farbstoff para-Phenylendiamin (PPD) handelt es sich um ein ubiquitäres Kontaktallergen mit einem hohen Sensibilisierungspotential. Es wurde berichtet, daß PPD oxidativen Streß erzeugt, und daß dieser möglicherweise in der präimmunologischen Phase der Sensibilisierung beteiligt ist. Das antioxidative Enzym Mangansuperoxiddismutase (MnSOD) übernimmt eine Schutzfunktion gegenüber diesen reaktiven Sauerstoffverbindungen. Im MnSOD-Gen lassen sich mehrere Polymorphismen nachweisen, die bereits als Risikofaktor für die Entstehung verschiedener Erkrankungen beschrieben worden sind. Beim Ala-9Val-Polymorphismus findet sich im Exon 2 eine Punktmutation an der Nukleotidposition 47 der mitochondrialen Signalsequenz und beim Ile58Thr-Polymorphismus im Exon 3 an der Nukleotidposition 339. Bei beiden kommt es zu einem Austausch der Base Thymin durch Cytosin. Ziel dieser molekularepidemiologischen Fall-Kontroll-Studie war es, einen Zusammenhang zwischen den erwähnten Polymorphismen und der individuellen Suszeptibilität für die Entstehung einer Kontaktsensibilisierung auf PPD aufzudecken und geeignete Methoden zu deren Nachweis zu etablieren. Untersucht wurde die DNA von 165 kaukasischen Patienten und 202 kaukasischen Kontrollpersonen. Für den Ile58Thre-Polymorphismus im MnSOD-Gen konnte ein Zusammenhang ausgeschlossen werden. Alle untersuchten Patienten wiesen das Thymin-Allel (Isoleucin) auf und keiner das risikobehaftete Cytosin-Allel (Threonin). Für den Ala-9Val-Polymorphismus zeigte sich In der vorliegenden Studie ebenso kein signifikanter Zusammenhang (P-Wert > 0,05). Tendenziell konnte jedoch im Patientenkollektiv im Vergleich zur Kontrollgruppe häufiger ein homozygoter Genotyp für das Cytosin-Allel (Alanin) nachgewiesen werden (27,4% vs. 22,9%, OR 1,3). Es wurde deutlich, daß die größten Unterschiede zwischen Patienten und Kontrollen bei den Frauen (28,9% vs. 24,1%, OR 1,3), den Personen älter als 45 Jahre (26,4% vs. 21,0%, OR 1,3) und den Frauen älter als 45 Jahren (24,5% vs. 17,9%, OR 1,5) vorlagen. Obwohl dieser Polymorphismus scheinbar keine große Rolle für die Kontaktsensibilisierung auf PPD spielt, deutet vieles darauf hin, daß das weibliche Geschlecht und ein höheres Lebensalter bzw. die Kombination aus beiden Faktoren die individuelle Suszeptibilität beeinflussen. Allergic contact dermatitis is a hypersensitivity reaction of the skin which is caused by a combination of environmental factors and individual susceptibility. The reason why one individual develops an allergic contact dermatitis whereas others are not affected even under long term allergen exposure is not completely understood. The dye para-phenylene diamine (PPD) is a very common and potent contact sensitizer in man. It has been found that oxidative stress from reactive oxygen species (ROS) may play an important role in the pre-immunological phase of allergic contact dermatitis to PPD. Manganese superoxide dismutase (MnSOD) is one of the primary enzymes that directly scavenge potential harmful oxidizing species. Several genetic polymorphisms in the MnSOD gene have been associated with various disease risks. A single nucleotide exchange from cytosine to thymine at position 47 in the mitochondrial targeting sequence in exon 2 results in an amino acid exchange at position -9 in the signal peptide from alanin to valine (Ala-9Val). The same nucleotide exchange at nucleotide position 339 in exon 3 results in an amino acid exchange at position 58 from threonine to isoleucin (Ile58Thr). The aim of this case-control study was to establish suitable methods for detection of polymorphisms Ala-9Val and Ile58Thr and to investigate their possible association with contact sensitization to PPD in humans. The study was performed in 165 unrelated Caucasian cases and 202 age- and gender matched Caucasian controls. As no heterozygous (CT) or homozygous carrier (CC) for Ile58Thr was found, an association of this polymorphism with contact sensitization to PPD can be excluded. For Ala-9Val no statistically significant differences for genotypes and allelic frequencies between cases and controls (p > 0.05) were detected. However, there was an increased number of persons homozygous for the cytosine allele (Ala) among cases (27.4% vs. 22.9%, OR = 1.3). This was especially evident for female cases (28.9% vs. 22.9%, OR = 1.3), subjects older than 45 years (26.4% vs. 21.0%, OR = 1.3) and female cases older than 45 years (24.5% vs. 17.9%, OR = 1.5). Although this polymorphism apparently has no strong impact on the individual susceptibility to develop a sensitization to PPD, these results may show an increased risk for females, especially of higher age.
... As UV radiation is not a risk factor for scrotal BCC, several theories have been put forward to explain this location. A recent study showed that genetic polymorphisms in loci coding for certain detoxifying enzymes could increase the risk of occurrence of these skin cancers [3]. Genital localization is considered a high-risk site for recurrence and distant metastases [4]. ...
Basal cell carcinoma is the most common malignant skin tumor. Its frequent in photo-exposed areas. Scrotal localization is exceptional, so we recommend analyzing any nodule evolving for more than 3 months outside professional exposure.
... In addition, many of the enzymes believed to be involved in the detoxification of UVA-induced ROS (including GSTT1, GSTM1 and NQO1) are also polymorphic in the human population and as such are also attractive candidates for influencing individual cancer susceptibility. GSTM1 and GSTT1 null genotypes have been consistently associated with individual susceptibility to basal cell carcinoma (BCC) (reviewed by Lear et al, 2000) but their role in the aetiology of CMM remains far less clear. NQO1 is an obligate two-electron reductase involved in detoxification reactions converting quinones to hydroquinines (Ross et al, 2000) preventing single-electron redox cycling reactions. ...
Cutaneous Malignant Melanoma (CMM) is a life threatening disease whose incidence and mortality rates have risen rapidly in the White Caucasian population in recent decades. The aim of the current study was to investigate the association between polymorphisms in genes involved in DNA-repair and detoxification of reactive metabolites and the development of CMM. The patient cohort consisted of 69 individuals while the control population consisted of 100 individuals. We found a statistically significant association between the presence of the wild type NQO1 C allele MDHFR C667T TS1494del6TSER polymorphisms and development of CMM P = 0.04 odds ratio = 2.35.The NQO1 CC genotype was more strongly associated with CMM development P = 0.016 odds ratio =2.92.The NQO1 gene codes for a protein that has been widely considered to be protective through its ability to detoxify quinones. However recent studies have also linked it to an important source of reactive oxygen and to NF-61547;B-dependent proliferation of cultured melanoma cells. In conclusion these results link molecular epidemiology and experimental evidence for the role of the NQO1 gene product in development of CMM. MDHFR and TS in Folic acid metabolism are responsible for methylation of methyl group. Two important roles of folate related to this study are the conversion of homocysteine to methionine and the generation of thymidylate (dTMP) which is required for DNA synthesis (Hayward, 2003). According to many studies done at this area, folate deficiency has been associated with chromosome strand breaks (Blount et al, 1997), impaired DNA repair ( Hayward, 2003), DNA hypomethylation and hypermethylation all of which have been associated with cancer cell formation (Simonetta et al 2001) (Dong-Hyun K. 2007). The result of study shows, MTHFR C677T and TS 6bp deletion/ insertion are not related to increased risk of CMM and therefore have no effect on an individuals susceptibility.
... So it has been proposed that genital papillomavirus 3 (HPV) infection might stimulate the growth of scrotal BCCs. Recent study found that genetic polymorphisms in loci coding for certain detoxifying enzymes might increase the risk of BCC development [3] . ...
Basal cell carcinoma (BCC) is the most commonly occurring carcinoma among humans. Reports of this lesion on nonexposed areas, such as the scrotum, soles, vulva, groin, pubic region, and axilla, are relatively uncommon. We present the case of a male patient with BCC located in the scrotum with a duration of 12 years who was successfully treated by local excision. Histopathology revealed infiltration by BCC. Our objective of this report is to remind specialists like urologists of the possibility of scrotal BCC when encountering scrotal lesions of unknown origin or not responding to topical treatments in a reasonable time frame.
... Numerous studies have investigated the genetic factors involved in the development of sporadic melanoma, including genes involved in the regulation of skin pigmentation, the cell cycle, DNA repair, the oxidative stress defense system and the production of immune modulatory mediators (5)(6)(7)(8)(9)(10)(11)(12). Previous evidence also suggested that patients with CMM mounted an efficient immune response towards the tumor leading in some cases to spontaneous regression, although in most cases these responses did not prevent tumor progression (13,14). ...
Cutaneous malignant melanoma (CMM) is one of the most immunogenic types of cancer, with a 6-fold higher rate of spontaneous regression than any other malignancy. In addition to responsiveness to different immunotherapies, the immunogenicity of CMM highlights the important role of the host immune system in the response to CMM. The present study aimed to explore the role of two functional promoter polymorphisms [IL6 -174G>C (rs1800785) and TNFA -308G>A (rs1800629)] in the regulation of the genes encoding the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-α, specifically in patients with CMM. A total of 76 patients with CMM and 200 control subjects were genotyped using PCR-restriction fragment length polymorphism. The genotype frequencies for both single nucleotide polymorphisms (SNPs) did not differ significantly between the patients and controls (P=0.358 and P=0.810 for IL6 and TNFA, respectively). However, compared with carriers of C-allele genotypes (CG+CC), patients with the IL6 -174GG genotype exhibited more advanced melanoma (Clark scale ≥3; P=0.037) and shorter survival times, particularly those who worked outdoors (in conditions with increased sunlight exposure; P=0.016). Furthermore, the serum IL-6 levels of patients with CMM were significantly higher than those of the control subjects, which were associated with unfavorable blood and serum characteristics and tumor progression (development of new distant metastases; P=0.004), and with a shorter overall survival time (P=0.042). Using a Cox proportional hazard model, the IL6 -174GG genotype was found to be an independent prognostic factor for reduced survival time (P=0.030), together with sex (being male; P=0.004) and occupations with higher exposure to sunlight (P=0.047). In conclusion, the results of the present study indicated that the promoter polymorphisms IL6 -174G>C and TNFA -308G>A are not predisposing factors for CMM. However, the IL6 -174G>C SNP and IL-6 serum concentrations are likely to influence the progression of the disease, and the GG genotype and higher IL-6 serum levels may indicate shorter survival.
... A large deletion (GSTM1*0 null variant) occurs hereditarily in about 50% of Caucasian population. The absence of active enzyme in subjects with the GSTM1*0/*0 genotype declines the efficiency of detoxification processes and leads to genotoxicity, toxic encephalopathy, higher cutaneous ultraviolet radiation erythemal sensitivity and risk of asbestosis or cancer (4)(5)(6)(7)(8)(9)(10). It is apparent that the activity of GSTM1 influences the level of BPDE and hence also the level of BPDE-DNA adducts. ...
Goeckerman therapy (GT) represents an effective treatment of psoriasis including a combination of pharmaceutical grade crude coal tar (CCT) and ultraviolet irradiation (UV-R). Coal tar contains a mixture of polycyclic aromatic hydrocarbons. The best known carcinogenic polyaromate - benzo[a]pyrene is metabolized into a highly reactive benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE). Glutathione S-transferase M1 (GSTM1) catalyses the conjugation of drugs, toxins and products of oxidative stress with glutathione. The aim of the study is to found possible associations between GSTM1 genotypes and the level of BPDE-DNA adducts in 46 psoriatic patients treated with GT. For genotyping, droplet digital PCR was applied. The GSTM1 copy number was normalized to β-globin reference gene. In five GSTM1*1/*1 subjects, the GSTM1 to β-globin ratio moved from 0.99 to 1.03 with a median of 1.01. GSTM1*0/*1 heterozygotes (n = 20) contained only one GSTM1 function allele which conditioned the ratio 0.47-0.53 (median 0.50). GSTM1*0/*0 individuals (n = 21) showed no amplification of the null variants because of the large deletion in GSTM1. BPDE-DNA concentrations ranged from 1.8 to 66.3 ng/µg with a median of 12.3 ng/µg. GSTM1*0/*0 and GSTM1*0/*1 genotypes showed non-significantly higher concentrations of BPDE-DNA adducts than the GSTM1*1/*1 one (12.3 and 12.4 vs 7.8 ng/µg). The non-significant relationship between BPDE-DNA adducts and GSTM1 genotypes in psoriatic patients could be associated with relatively low doses of CCT and short-term UV-R exposures used in GT.
... UV A is less mutagenic than is UV B and causes indirect DNA damage via a photo-oxidative stress-mediated mechanism, resulting in formation of reactive oxygen species, which interact with lipids, proteins and DNA to generate intermediates that combine with DNA to form adducts [62]. Several complex DNA repair systems are needed to prevent the harmful effects of these premutagenic adducts [63]. ...
Purpose: Cutaneous malignancies are the most common human cancers, and despite growing public awareness of the harmful effects of sun exposure, incidence and morbidity continue to rise which has generated great interest in unravelling of their aetiology and in the search for new non-invasive treatment strategies. Methods: A yearly increase in incidence of cutaneous malignancies has been reported since a long time worldwide, suggesting that prevalence of this cancer will soon equal that of all other cancers combined. Grouping of various skin lesions and malignancies under a common umbrella term poses challenges because clear differences exist in their aetiopathogenesis, clinical course and management strategies, suggesting the need of the novel and future therapeutic perspectives for the treatment from nanotechnology to immunotherapy. Results: Moreover, treatment modalities should comprised of gold standards of the current recommended therapies worldwide and the actual needs of these patients. Conclusion: The overall goal of this review was to explore the approaches for cutaneous malignancies’ new technological methods instead of new molecules.
... Several studies, including our own, have shown that individuals who are deletion homozygote for GSTM1 or GSTT1, as well as individuals that present GSTP1 variants (GSTv) resulting from an aminoacid substitution (1105Valine) at exon 5 of GSTP1, are at increased risk for a series of tumors [2][3][4]7,8 . GST enzymes are implicated in the detoxification of lipid and DNA products of UVR-derived oxidative stress and allelic variants at GSTs are associated with outcome of various oxidative-stress related diseases, including skin cancer [9][10][11][12][13] . ...
... Robust and complex DNA repair mechanisms are required to prevent the harmful effects of UVR-induced DNA damage and such adduct formation [128,129]. In addition, it appears that solar radiation early in life may result in persistent DNA damage such as DNA fragmentation and mitochondrial DNA deletions, and altered patterns of gene expression such as decreased RAD23 UVR excision repair and Growth Arrest and DNA Damage (GADD45) expression [130]. Thus, the capacity of the host to repair DNA damage is also a key factor in skin carcinogenesis. ...
Skin cancer is the most common malignancy in humans, likely due to its location at the interface between internal and external environments and exposure to multiple carcinogens, mostly ultraviolet radiation (UVR) and human papillomaviruses (HPV). With increased longevity, changing patterns of sun exposure and greater UVR reaching the earth's surface due to ozone depletion, the incidence of skin cancer is steadily increasing worldwide. Moreover, skin cancer, mostly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (collectively known as non-melanoma skin cancer (NMSC), is a substantial public health concern and one of the largest Medicare health expenditures. Individuals presenting with skin cancer are at high risk for synchronous and metachronous second primary skin cancers. This phenomenon is known as "field cancerization", where the entire cutaneous site affected is presumed to be mutagenized and is therefore at risk for multiple cancers. The recent application of molecular technologies to the examination of peri-lesional and more distant adjacent normal skin samples has demonstrated many of the genotypic aberrations found in cancer. These defects are the earliest changes of oncogenesis that occur in a stepwise, cumulative fashion culminating in metastatic cancer via initiation, promotion, selection, and clonal expansion. Moreover, these findings implicate two distinct levels of field cancerization: 1) molecular progression where histologically normal cells accumulate genomic damage; and 2) phenotypic progression denoted by evolution of histologically normal skin to precursors to in situ cancer that can be followed by invasion and ultimately metastatic disease. Phenotypic progression is also characterized by the expansion of genetically damaged tumor cells in the modified environment that facilitate tumor growth and suppress the host response. In this model, the cutaneous field develops a "tumor stem cell", which acquires a growth advantage and exhibits a "mutator phenotype" [i.e. genomic instability (GIS)] that enables it to expand beyond its histologically defined stem cell niche, form diverse clonal fields, and accrue further genetic alterations that eventuate into invasive cancer. GIS is manifested as single base mutations, gain or loss of whole or partial chromosomes, amplification of oncogenes, mismatch repair gene defects, and epigenetic alterations including hypermethylation of promoter DNA of key tumor suppressor genes, or genomic incorporation of the oncogenic HPV. The facilitating environment for tumor growth represents the local production of factors that allow the tumor cells to escape the immune system, to leave the tumor stem cell niche and expand into the surrounding environment. In this chapter, we review the epidemiologic evidence of field cancerization; etiologic factors that lead to genomic instability in the skin; the stem cell niche where cancer-causing genetic defects are most likely to be initiated, and from which the mutated clone must expand beyond; host factors that augment and accelerate the process such as immunosuppression; and the growing body of evidence that supports the concept of cutaneous field cancerization. Moreover, we discuss the potential utilization of field effect biomarkers in risk assessment, cancer prevention, margin control, and prognosis.
... Some authors investigated cytochrome p450 in the skin structure. They found that in the epidermis, sweat glands and hair follicles exists cytochrome p450 and its activity is much better then in the liver (2,5,7,10,11,13). The third important mechanism is trauma. ...
The pathogenesis of the skin lesions in acute intoxications is still not clear and the strict mechanism is not defined. Our 10 year investigation reveals considerable relationship between skin lesions appearance and frequency of coma status (RR = 25.59±2.53) and other clinical and laboratory factors connected with the coma. We discussed some mechanisms that may be important to form the skin lesions: 1.Neurotoxicants interacted with neuromediathors in CNS and their trophic function to skin cells is disturbed. 2.Neurotoxicants interacted with the skin microcirculation (permeability and motility) by three ways: direct toxic interaction; through neuromediathors and through vessel's obstructions when there is pressure or fixation. 3.Through other trophic metabolites (CO2, ATP, lactat, cADP, cAMP) in cells and interstitial space. 4. We discuss some hypothesis connected with the direct toxic mechanism of skin cell damage: through xenobiotics microsomal oxidation with cytochrome P450 and forming free oxygen species and in consequence - damage of the cells membrane; through excretion by sweat glands and hair follicles.
... Herein we report analyses from three pooled colonoscopy-based case-control studies of incident, sporadic colorectal adenoma to investigate whether the association between the OBS and colorectal adenoma may vary according to SOD2, CAT, and GSTP1 genotypes [7,[10][11]. ...
Purpose:
Previous research found inverse associations between oxidative balance and risk of colorectal adenoma. However, these measures were limited to extrinsic (dietary and lifestyle) exposures and did not account for intrinsic factors, specifically antioxidant enzymes responsible for cellular defense against oxidative stress. We investigated whether the association between an oxidative balance score (OBS) and colorectal adenoma may vary according to polymorphisms in genes that encode three antioxidant enzymes: Manganese superoxide dismutase (SOD2), catalase (CAT), and glutathione-S-transferase P1 (GSTP1).
Methods:
Using data pooled from three colonoscopy-based case-control studies of incident, sporadic colorectal adenoma, we constructed an OBS reflecting pro- and antioxidant exposures. We used multivariable logistic regression to assess whether the association between the OBS and colorectal adenoma differed according to polymorphisms in the genes encoding the antioxidant enzymes.
Results:
OBS was inversely associated with colorectal adenoma; adenoma risk was not associated with the genetic polymorphisms, and there was no consistent pattern of effect modification by individual genotypes or combined gene scores.
Conclusions:
Variations in the antioxidant enzyme genes SOD2, CAT, and GSTP1 do not seem to substantially modify associations of environmental exposures related to oxidative balance with risk for sporadic colorectal adenoma.
... GSTM1 catalyzes the conjugation of DNA hydroperoxides, namely, 4-hydroxynonenal, linoleic acid hydroperoxide which are mutagenic and cytotoxic product of lipid peroxidation [37]. Further, 5-hydroxymethyluracil, a mutagenic compound that is formed by either oxidative attack on the methyl group of the thymine base of DNA or from deamination of products formed by oxidation of 5-methylcytosine was also taken care by GSTM1 [38]. Skin allergies are more common among individuals with genetic absence of GSTM1 [39]. ...
We studied the effect of genetic susceptibility on hexavalent chromium induced dermal adversities. The health status of population was examined from the areas of Kanpur (India) having the elevated hexavalent chromium levels in groundwater. Blood samples were collected for DNA isolation to conduct polymorphic determination of genes, namely: NQO1 (C609T), hOGG1 (C1245G), GSTT1, and GSTM1 (deletion). Symptomatic exposed subjects (n = 38) were compared with asymptomatic exposed subjects (n = 108) along with asymptomatic controls (n = 148) from a non contaminated reference community. Exposed symptomatic group consisted of 36.8% subjects who were GSTM1 null genotyped as compared to asymptomatic where only 19.4% subjects were null. The exposed subjects with GSTM1 null genotype were more susceptible to dermal adversities in comparison with wild genotyped subjects (OR = 2.42; 95% CI = 1.071-5.451). Age, smoking, gender or duration of residence were not found to have any confounding effect towards this association. Association with other genes was not statistically significant, nonetheless, possible contribution by these genes cannot be ruled out. In conclusion, variation in the polymorphic status of GSTM1 gene may influence dermal outcomes among residents from Cr(VI) contaminated areas. Further studies are therefore, needed to examine these observations among different population groups.
... CYP and GST are known to detoxify mutagens, whilst p53 has an important function as a tumour suppressor gene regulating the cell cycle. [17][18][19] Whilst sporadic BCC develops de novo, SCC arises from precursor lesions of actinic keratosis (AK) and Bowen's disease, and represents a multistep accumulation of genetic damage. Over 72% of SCC have been noted to develop within AK or actinically damaged skin, also known as background field cancerisation. ...
Nonmelanoma skin cancer (NMSC) represents the most common form of cancer in Caucasians, with continuing increase in incidence worldwide. Basal cell carcinoma (BCC) accounts for 75% of cases of NMSC, and squamous cell carcinoma (SCC) accounts for the remaining majority of NMSC cases. Whilst metastasis from BCC is extremely rare, metastasis from high-risk SCC may be fatal. In this article, we review the aetiology, diagnosis and management of NMSC.
... UVA and UVB radiation cause indirect damage to DNA by inducing oxidative stress (Griffiths et al, 1998, Crit Rev Clin Lab Sci). Reactive oxygen species thus produced, interact with lipids, proteins and DNA to generate intermediates that combine with DNA to form adducts (Lear et al, 2000, Br J Dermatol). The authors have focused on the extensive clinical diversity following initial presentation, demonstrated by patients to identify subgroups that are associated with different risks of developing tumours. ...
... Cytochrome 450 (CYP) and glutathione S-transferase (GST) are both involved in detoxifying various mutagens. Specific polymorphisms within these supergenes have been identified, in particular GSTM1, GSTT1, GSTP1 and CYP2D6 [17,18]. CYP2D6 may be associated with the development of multiple BCCs also [19]. ...
Nonmelanoma skin cancers (NMSCs), which include basal and squamous cell cancers are the most common human cancers. BCCs have a relatively low metastatic rate and slow growth and are frequently underreported. Whilst there is a definite role of sunexposure in the pathogenesis of BCC, several additional complex genotypic, phenotypic and environmental factors are contributory.
The high prevalence and the frequent occurrence of multiple primary BCC in affected individuals make them an important public health problem. This has led to a substantial increase in search for newer noninvasive treatments for BCC. Surgical excision with predetermined margins remains the mainstay treatment for most BCC. Of the newer non-invasive treatments only photodynamic therapy and topical imiquimod have become established in the treatment of certain BCC subtypes, while the search for other more effective and tissue salvaging therapies continues. This paper focuses on the pathogenesis and management of BCC.
... chromosome, with loss of heterozygosity. This gene is involved in a great variety of processes such as the embryogenesis, homeostasis maintenance in the old tissues, tissue repairing during the persistent chronic inflammation and carcinogenesis [18, 19]. Although the understanding of BCC pathogenesis is greatly improved, incidence of the disease is steadily increasing , and the surgeon's task is to assess the best BCC management. ...
Introduction. Basal cell carcinoma (BCC) is a locally invasive malignant epidermal tumour. Incidence is increasing by 10% per year; incidence of metastases is minimal, but relapses are frequent (40%–50%). The complete excision of the BCC allows reduction of relapse. Materials and Methods. The study cohort consists of 1123 patients underwent surgery for basal cell carcinoma between 1999 and 2009. Patient and tumor characteristics recorded are: age; gender; localization (head and neck, trunk, and upper and lower extremities), tumor size, excisional margins adopted, and relapses.
Results. The study considered a group of 1123 patients affected by basal cell carcinoma. Relapses occurred in 30 cases (2,67%), 27 out of 30 relapses occurred in noble areas, where peripheral margin was <3 mm. Incompletely excised basal cell carcinoma occurred in 21 patients (1,87%) and were treated with an additional excision.
Discussion. Although guidelines indicate 3 mm peripheral margin of excision in BCC <2 cm, in our experience, a margin of less than 5 mm results in a high risk of incomplete excisions.
... Of these, GSTT1 is responsible for the biotransformation of the constituents of tobacco smoke, such as alkyl halides, and its derivatives, such as monohaloethanes, ethylene oxide, benzo(a)pyrene diol epoxide, and acrolien (Pemble et al., 1994;Rebbeck, 1997). GSTM1 subfamily metabolizes lipid peroxidation products, DNA hydroperoxides, and polyaromatic hydrocarbons such as benzo [alpha] pyrene (Lear et al., 2000;Ye et al., 2004;Jain et al., 2006). The GSTP1 enzyme is widely expressed in tumor cells and is responsible for the detoxification of benzo(a)pyrene diol epoxide and acrolein present in cigarette smoke. ...
Widespread use of tobacco and betel quid consumption and a high incidence of tobacco-associated aerodigestive tract cancers have been reported in different ethnic groups from several regions of Northeast (NE) India. This study was done to explore the possibility of phase II metabolic enzymes being responsible for the high prevalence of cancers in this region of India.
Samples from 370 cases with oral, gastric, and lung cancers and 270 controls were analyzed for polymorphism of glutathione-S-transferase (GST) genes using polymerase chain reaction-restriction fragment length polymorphism-based methods.
Tobacco smoking and betel quid chewing were found to be high risk factors for oral and lung cancers but not for gastric cancer, whereas tobacco chewing was found to be a risk factor for oral cancer but not for gastric or lung cancer. The variant genotypes of GSTP1 were not associated with any of the aerodigestive tract cancers. GSTT1 and GSTM1 null genotypes appeared to play a protective role for lung cancer (odds ratio [OR] = 0.47, 95% confidence interval [95% CI]: 0.24-0.93, p = 0.03) and (OR = 0.52, 95% CI: 0.28-0.96, p = 0.04), but they were not associated with oral and gastric cancers. However, when data was analyzed in different geographic regions the GSTT1 null genotype was found to be a significant risk factor for oral (OR = 2.58, 95% CI 1.01-6.61, p = 0.05) as well as gastric cancer (OR = 3.08, 95% CI 1.32-7.19, p = 0.009) in samples obtained from the Assam region of NE India. This is the first study on the association of GST polymorphisms and aerodigestive tract cancers in the high-risk region of NE India.
... It has been suggested that NMSC on sun-protected anatomic sites may occur in individuals with decreased DNA repair capacity (62,118). Glutathione-S-transferase (GST) detoxifies DNA and lipid products of oxidative stress, and thus inherited polymorphisms within the GST family of genes may predispose to BCC (119). Also, the xeroderma pigmentosum group D (XPD) gene encodes a helicase, that participates in both NER and basal transcription as part of the transcription factor TFIIH (120). ...
Basal cell carcinoma (BCC) is the most common skin cancer in white populations with an increasing incidence worldwide, thereby imposing an important public health problem. Its etiology is still unclear, but existing data indicate that the risk for BCC development is of multifactorial origin and results from the interplay of both constitutional and environmental factors. Yet, UV radiation (UVR) is believed to be the predominant causative risk factor in the pathogenesis of BCC. For years, BCC and squamous cell carcinoma (SCC) have been grouped together as "nonmelanoma skin cancer." However, it seems that there are considerable biologic differences between BCC and SCC, and thus each type of epithelial cancer should be addressed separately. The present review provides an overview of the intriguing etiologic link of BCC with UVR and attempts a comprehensive review of recent epidemiologic and molecular evidence that supports this association.
... The glutathione-S-transferases are involved in the protection against oxidative stress on the skin, and cytochrome P450 (CYP) enzymes are involved in detoxification of numerous xenobiotics including carcinogenic components of tobacco smoke. 132,133 The polymorphism displayed by these gene families make them obvious candidates for affecting cancer susceptibility as reduced ability to remove potential carcinogens may result in mutations in key tumour suppressor genes. An increase in skin tumorigenesis has been seen in mice lacking the p-class glutathione-S-transferase. 134 Associations with BCC have been seen in immunosuppressed people, those with Gorlin syndrome, people with multiple BCC, and in the general population although no single glutathione-S-transferase or CYP enzyme gene has consistently shown to affect risk. ...
Basal cell carcinoma is the most common human malignancy in populations of European origin, and Australia has the highest incidence of basal cell carcinoma in the world. Great advances in the understanding of the genetics of this cancer have occurred in recent years. Mutations of the patched 1 gene (PTCH1) lead to basal cell carcinoma predisposition in Gorlin syndrome. PTCH1 is part of the hedgehog signalling pathway, and derangements within this pathway are now known to be important in the carcinogenesis of many different cancers including sporadic basal cell carcinoma. The molecular biology of the hedgehog pathway is discussed, and mouse models of basal cell carcinoma based on this pathway are explored. New developments in non-surgical treatment of basal cell carcinoma are based on this knowledge. Other genes of importance to basal cell carcinoma development include the tumour suppressor gene P53 and the melanocortin-1 receptor gene. In addition, we discuss molecules of possible importance such as the glutathione-S-transferases, DNA repair genes, cyclin-dependent kinase inhibitor 2A, Brahma and connexins. Evidence of familial aggregation of this cancer is explored and supports the possibility of genetic predisposition to this common malignancy.
... Eine Behandlung der glatten Muskulatur des Respirationstraktes mit INF-γ zeigte jedoch eine erhöhte Expression des CysLTR1 (Amrani et al., 2001) SNPs eine genetische Empfindlichkeit für verschiedene Erkrankungen oder Reaktionen auf Medikamente widerspiegeln (Wang et al., 1998). Hauterkrankungen wie die atopische Dermatitis (Cox et al., 1998), die Psoriasis (Asadullah et al., 2001) und für maligne Hauttumore (Lear et al., 2000 Expression des Rezeptors verändert war (Duan et al., 2003) bereitstellen. Die Konzentration des Enzyms Phopholipase A 2 ist ebenfalls erhöht (Calabrese et al., 2000). ...
Azetylsalizylsäure (Aspirin®) gehört zu den am häufigsten verwendeten Arzneimitteln der Welt. Die Bedeutung von Aspirin® liegt vor allem in der Anwendung als Analgetikum, jedoch auch als Thrombozytenaggregationshemmer in der Prävention bei myokardialen sowie zerebralen Durchblutungsstörungen. Die Prävalenz einer Intoleranz auf ASS wird mit 0,3 bis 0,9% der Gesamtbevölkerung angegeben. Wichtig bei der ASS-Intoleranz ist, dass es zu Kreuzreaktionen mit NSAIDs kommen kann, so dass es sich meist um eine Analgetika-Intoleranz handelt. Der Pathomechanismus der ASS-Intoleranz ist noch nicht ausreichend geklärt. Die Wirkung von ASS erfolgt durch die Hemmung der Cyclooxygenasen, wodurch die Prostaglandinsynthese vermindert wird. Dadurch wird die vorhandene Arachidonsäure über die Lipoxygenase zu Leukotrienen verstoffwechselt, die in akute und chronische Entzündungsreaktionen involviert sind. Ihre Wirkungen entfalten sie durch Interaktion mit spezifischen Rezeptoren, die als Cysteinyl-Leukotrienrezeptoren (CysLTR) bezeichnet werden. Verfolgt man den Syntheseweg der Leukotriene, so sind zur Aufklärung der ASS-Intoleranz verschiedene Ansatzpunkte möglich. In dieser Arbeit wurden die Leukotrienrezeptoren CysLTR1 und CysLTR2 auf genetische Varianten mit Hilfe der Sequenziertechnik untersucht. Im CysLTR1 zeigte sich eine Sequenzvariante an der Position 927 (Thymin -> Cytosin) im kodierenden Bereich (C Terminus). Die weitere Bedeutung der Variante für den Phänotyp ASS-Intoleranz wurde anschließend in einer Fall-Kontrollstudie geprüft. Insgesamt wurden 133 Fälle und 270 Kontrollen analysiert. Die Häufigkeit des Polymorphismus war in der Fallgruppe signifikant höher als in der Kontrollgruppe (OR 2,04, KI: 1,271-3,282). Da sich das Gen für diesen Rezeptor auf dem X-Chromosom befindet, erfolgte eine geschlechtsabhängige Betrachtung. Innerhalb des weiblichen Kollektivs war die Häufigkeit in der Fallgruppe signifikant höher als in der Kontrollgruppe (OR 1,89, KI: 1,09-3,277). Inwieweit dieser Polymorphismus andere Faktoren beeinflusst, bleibt Gegenstand weiterer Untersuchungen. Insgesamt liefert diese Arbeit einen neuen Ansatzpunkt zur weiteren Aufklärung des Pathomechanismus der ASS Intoleranz. Acetylsalicylic acid (Aspirin) is one of the most frequently used drugs in the world. The importance of aspirin is not only the role as an analgesic, it is also used in the prophylaxis of ischemic heart desease and strokes. The aspirin-intolerance occurs in 0,3-0,9% of the general population. Important is that a cross reaction to other nonsteroidal anti-inflammatory drugs (NSAID) is possible. The pathogenesis is not sufficient cleared. Aspirins target is to inhibit the cyclooxygenase. This leads to a decrease in the level of prostaglandin biosynthesis. The arachidonic acid is metabolised by the lipoxygenase to leukotrienes. Leukotrienes are involved in several inflammatory processes. Leukotrienes act on two G protein-coupled receptors, CysLTR 1 and CysLTR 2. There are different starting points in the biosynthesis of the leukotrienes to try to clear the aspirin-intolerance. In this study the leukotriene receptors CysLTR 1 and CysLTR 2 were analyzed to genetic variants. A single nucleotide exchange from thymine to cytosine at position 927 (927 T -> C) was found in the coding region for receptor 1 (C-terminus). The next step was to analyze DNA of 133 cases and 270 age-and gender-matched controls for the presence of this polymorphism. This analysis shows the frequency of the polymorphism is statistically significant higher in the cases. (OR 2,04, CI: 1,271-3,282). Furthermore it was found that TC- and CC-carriers among females (the gene for CysLTR 1 is located on X chromosome (Xq13-q21)) are statistically significantly increased (OR 1,89, CI: 1,09-3,277).
... Polymorphically expressed glutathione S-transferases such as GSTT1 ( SchroÈ der et al. 1996) and GSTM1 ( Bell et al. 1992) might therefore modulate the risk of being aected by thimerosal sensitization. These functionally relevant polymorphisms were held to in¯uence the risk of chemically induced carcinogenesis ( Rebeck 1997) or cutaneous malignancies ( Lear et al. 2000), and might even determine allergenic properties of sensitizers. Since thimerosal allergy is a strictly substance-related disease, associations with polymorphic enzymes possibly involved in the metabolism of its decomposition products might be particularly pronounced. ...
Thimerosal is an important preservative in vaccines and ophthalmologic preparations. The substance is known to be a type IV sensitizing agent. High sensitization rates were observed in contact-allergic patients and in health care workers who had been exposed to thimerosal-preserved vaccines. There is evidence for the involvement of the glutathione system in the metabolism of thimerosal or its decomposition products (organomercury alkyl compounds). Thus detoxification by polymorphically expressed glutathione S-transferases such as GSTT1 and GSTM1 might have a protective effect against sensitization by these substances.
To address this question, a case control study was conducted, including 91 Central European individuals with a positive patch-test reaction to thimerosal. This population was compared with 169 healthy controls and additionally with 114 individuals affected by an allergy against para-substituted aryl compounds. The latter population was included in order to test whether possible associations were due to substance-specific effects, or were a general feature connected with type IV immunological diseases. Homozygous deletions of GSTT1 and GSTM1 were determined by polymerase chain reaction.
Glutathione S-transferase M1 deficiency was significantly more frequent among patients sensitized to thimerosal (65.9%, P = 0.013) compared with the healthy control group (49.1%) and the "para-compound" group (48%, P = 0.034). Glutathione S-transferase T1 deficiency in the thimerosal/mercury group (19.8%) was barely elevated versus healthy controls (16.0%) and the "para-compound" group (14.0%). The combined deletion (GSTT1-/GSTM1-) was markedly more frequent among thimerosal-sensitized patients than in healthy controls (17.6% vs. 6.5%, P = 0.0093) and in the "para-compound" group (17.6% vs. 6.1%, P =0.014), revealing a synergistic effect of these enzyme deficiencies (healthy controls vs. thimerosal GSTM1 negative individuals, OR = 2.0 [CI = 1.2-3.4], GSTT1-, OR = 1.2 [CI = 0.70-2.1], GSTM1/T1-, OR = 3.1 [CI = 1.4-6.5]).
Since the glutathione-dependent system was repeatedly shown to be involved in the metabolism of thimerosal decomposition products, the observed association may be of functional relevance.
Basal cell carcinomas (BCCs) are the commonest of the non‐melanoma skin cancers and are the most common human cancers. Their rising incidence and associated morbidity has generated phenomenal interest in unravelling their pathogenesis, which has also led to a keen interest in the search for newer potential non‐invasive treatments. Unlike other non‐melanoma skin cancers, the relationship between sun‐exposure patterns and pathogenesis of the various subtypes of BCC still remains undetermined. Besides, several complex genotypic, phenotypic and environmental factors contribute to the pathogenesis of BCCs, which are mainly diagnosed clinically. Histology helps in the clinical confirmation of diagnosis and to subtype the BCC. The dermatologist now has several treatment options for BCCs. These range from non‐invasive, topical and photodynamic therapies for superficial BCCs to Mohs micrographic surgery for more complex lesions. The search for other more effective and tissue salvaging therapies continues.
Detection of lymph node micrometastasis can be useful in determining prognosis, staging, and treatment options for some malignancies. As a result, the use of lymphatic mapping and sentinel lymph node biopsy (LM/SLNB) has become an important and widely used tool in the evaluation of various noncutaneous and cutaneous tumors, especially melanoma.
Nonmelanoma skin cancer (NMSC) is the most common type of cancer in Caucasians. There are various environmental and genetic factors implicated as causative agents for NMSC. Ultraviolet (UV) radiation is the most significant risk factor for NMSC. Basal cell carcinoma (BCC) arises from the pluripotent cells in the basal layer of the epidermis, and rarely from the outer root sheath of hair follicles, sebaceous glands or other cutaneous appendages. Squamous cell carcinoma (SCC) is a malignant tumor of keratinocytes arising in the epidermis. It is often seen developing from pre‐existing precancerous lesions. Radiotherapy is an effective treatment modality for patients with NMSC who are not eligible candidates for surgery. The psychological impact of skin cancer and the role of stress in the development of skin cancer is dealt with in the emerging field of psychodermato‐oncology. Larger studies should be conducted to further investigate the use of botanical agents for skin cancer.
Basal cell carcinomas (BCCs) are the most common malignant (cutaneous) neoplasms worldwide, with an incidence of approximately 2.8 million in the United States. The lifetime risk of developing a BCC is about 30 % in Caucasians, and most of the tumors develop in patients older than 50 years of age. Individuals with Fitzpatrick type I and II complexions have the highest risk of developing BCC. Though exposure to the ultraviolet component of sunlight is the most common cause, about 0.27 % cases of BCC occur in the non-sun-exposed genital skin.
Das Basalzellkarzinom ist der häufigste Tumor des Menschen, mit kontinuierlich zunehmender Inzidenz. Für die USA wird derzeit mit einer Zahl von etwa 750.000 Patienten pro Jahr und einer jährlichen Zuwachsrate zwischen 3–10% gerechnet [1]. Statistisch besteht für nach 1994 geborene Kaukasier eine 30%ige Wahrscheinlichkeit, in ihrem Leben ein Basalzellkarzinom zu bekommen. Das Erkrankungsrisiko ist dabei sowohl von genetischen Faktoren, einschließlich des individuellen Hauttyps, als auch von der Exposition gegenüber exogenen Noxen, das heißt insbesondere UVB-Strahlung, abhängig. Die molekularen Mechanismen, die zur Entstehung von Basalzellkarzinomen führen, sind dabei erst ansatzweise verstanden. Einen Meilenstein stellte diesbezüglich die Identifizierung des Gens dar, das für das Gorlin-Syndrom verantwortlich ist [3] Ausgehend von den Erkenntnissen über diese seltene Erbkrankheit ergaben sich somit neue Anknüpfungspunkte auch in Bezug auf die Entstehung der sporadischen Basalzellkarzinome.
Cancer results from a complex interaction of environmental and genetic factors that impact upon a target cell, eventually leading to uncontrolled growth, invasion of adjacent structures and metastatic dissemination. Recent advances in understanding the mechanisms of carcinogenesis have emphasized the role of molecular pathways leading to cancer, raising expectations among clinicians and the public that many of today’s common afflictions will be prevented or definitively treated in the future. This chapter seeks to integrate the findings from the molecular and epidemiological paradigms, and in so doing, highlight salient issues of relevance to the control of skin cancer.
he common types of skin cancer (basal cell carcinoma, squamous cell carcinoma and melanoma) are becoming increasingly common. This chapter reviews the genetic basis of these common skin cancers.The clinical features of the three common types are described followed by discussion of the identified common lower penetrance susceptibility genes. Rarer familial genetic conditions associated with these cancers including nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome), Bazex-Dupre-Christol syndrome, xeroderma pigmentosum, multiple self-healing epitheliomas of Ferguson Smith and familial malignant melanoma will be reviewed.
Besides genetic susceptibility, several environmental risk factors play an important role in the pathogenesis of non-melanoma skin cancer (NMSC). Role of ultraviolet radiation (UVR) in patho-genesis of NMSC in general is well established; however, its effect on the pathogenesis of different basal cell carcinoma (BCC) subtypes is still a matter of research. Ultraviolet radiation in the wavelengths 290- 320 nm (UVB) is the most carcinogenic range of terrestrial UVR. In contrast to squamous cell carcinomas (SCCs), intermittent rather than chronic sun exposure may be more important in the development of superficial BCC. The ratio of SCC to BCC in the setting of iat-rogenic immunosuppression reverses as SCC occurs more frequently in the transplant recipients.
Occupational skin cancer can be induced due to industrial exposure to chemical carcinogens, but nowadays more important due to occupational exposure to UV radiation (UVR). Occupational skin cancer is characterized by long induction periods (years or decades) and its first manifestation is often seen many years after the occupational exposure or even when the affected individuals are not more occupationally exposed. Important industrial chemicals are arsenic and inorganic arsenic compounds, polycyclic aromatic hydrocarbons (PAHs) with particularly high levels in brown coal tars (soft coal tars), coal tars (black coal tars), coal tar pitches, coal tar oils, and coke oven emissions and can cause basal cell carcinomas and squamous cell carcinomas. A recently published systematic appraisal of the epidemiologic literature and meta-analysis clearly indicates that occupational UV-light exposure is a substantial and robust risk factor for the development of cutaneous squamous cell carcinoma (SCC). The actually available evidence of the epidemiologic literature could also clearly show a significant risk increase for occupationally UV-exposed workers to develop basal cell carcinoma (BCC) compared to nonexposed workers. There is enough scientific evidence that outdoor workers have an increased risk to develop work-related occupational skin cancer due to natural UVR exposure and adequate prevention strategies have to be implemented. The three measures that are successful and of particular importance in the prevention of nonmelanoma skin cancer in outdoor workers are the following: 1. Changes in behavior regarding awareness of health and disease resulting from exposure to natural UV radiation 2. Protection from direct UV radiation by wearing suitable clothing 3. Regular and correct use of appropriate sunscreens
Introduction: The vascular endothelial growth factor (VEGF) is involved in pathologic angiogenesis in several neoplasms. Several functional single nucleotide polymorphisms (SNPs) in the promoter region have been described. It has been suggested that -1154G/A polymorphism is associated with VEGF expression. Aim: The aim of our study was to evaluate the connection between -1154G/ A VEGF gene polymorphism and BCC susceptibility. Material and methods: We analyzed 100 patients with BCC and 240 healthy controls. The -1154G/A polymorphism in the promoter region of the VEGF gene was analyzed by amplification refractory mutation system-polymerase chain reaction. The result was evaluated by the χ2 test with Yates correction. Results: We have found that AA genotype frequency was significantly decreased among patients with BCC in comparison with control subjects (3 vs. 16.2%, p = 0.0014). We also found that VEGF-1154 A allele frequency was significantly decreased among patients with BCC in comparison with control subjects (30.5 vs. 40.0%, p = 0.0246). Conclusions: This is the first report concerning VEGF gene polymorphism and BCC. Presented data suggest that the SNP at position -1154 of the promoter region of the VEGF gene may play a role in pathogenesis of BCC.
Skin cancer is by far the most common kind of cancer diagnosed in many western countries and ultraviolet radiation is the most important risk factor for cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Although employees at several workplaces are exposed to increased levels of UV radiation, skin cancer due to long-term intense occupational exposure to UV radiation is often not considered as occupational disease. The actually available evidence in the epidemiological literature clearly indicates that occupational UV radiation exposure is a substantial and robust risk factor for the development of cutaneous SCC and also clearly shows a significant risk for developing BCC. There is enough scientific evidence that outdoor workers have an increased risk of developing work-related occupational skin cancer due to natural UV radiation exposure and adequate prevention strategies must be implemented. The three measures which are successful and of particular importance in the prevention of nonmelanoma skin cancer in outdoor workers are changes in behaviour regarding awareness of health and disease resulting from exposure to natural UV radiation, protection from direct UV radiation by wearing suitable clothing, and regular and correct use of appropriate sunscreens.
Nonmelanoma skin cancer and related premalignant lesionsThe molecular and cellular biology of nonmelanoma skin cancerGeneral principles in the management of patients with nonmelanoma skin cancerPremalignant epithelial lesionsBenign epidermal tumoursCysts
Non-melanoma skin cancer and related premalignant lesions The molecular and cellular biology of non-melanoma skin cancer General principles in the management of patients with non-melanoma skin cancer Premalignant epithelial lesions Benign epidermal tumours Cysts References
Basal cell carcinomas and squamous cell carcinomas are the most common human cancers and increasing in incidence. The development of novel, pathogenesis-based therapies requires a better knowledge of the molecular mechanisms leading to the development of these tumors. Basal cell carcinomas are characterized by aberrant activation of Sonic-Hedgehog (SHH) signaling due to mutations in the PTCH or SMOH genes. In addition, about 50% of the cases carry mutations in the TP53 tumor suppressor gene. Squamous cell carcinomas lack alterations of SHH signaling, while TP53 mutations are detectable in virtually all cases. Alterations in cell cycle regulatory genes, such as CDKN2A, are also common. Recently, specific inhibitors of the SHH-signaling pathway have been developed and shown promising results in preclinical studies on experimental basal cell carcinomas. However, the clinical significance of such targeted molecular therapy remains to be evaluated. Another successful pathogenesis-based therapy, which is already in clinical use, is the administration of topic immune response modifier imiquimod. This drug can eradicate non-melanoma skin cancers by different mechanisms, including cytokine-mediated stimulation of the anti-tumor immune response, as well as the induction of tumor cell apoptosis.
Background Polymorphous light eruption (PLE) is the most common chronic and idiopathic photodermatosis. PLE is assumed to represent an immunological hypersensitivity reaction to a radiation-induced cutaneous antigen involving reactive oxygen species (ROS) on the basis of a genetic predisposition. Among others, cellular protection against ROS is provided by glutathione S-transferases (GSTs). Different variants of the GST enzymes may influence the activity and efficiency of detoxification and biotransformation of unknown UV-induced skin-antigens and other factors that may play an important role in the pathogenesis of PLE.
Methods In this study the relationship between isoenzymes of the GST genes GSTM1, GSTT1 and GSTP1 and possible protective or predisposing effects on PLE was examined in 29 patients and 144 controls. Diagnosis of PLE was based on the presence of characteristic clinical features.
Results No association between the functional polymorphisms of the GST gene family and PLE was found. Prevalence of certain GST isoenzymes or polymorphisms in patients with PLE did not differ from healthy controls.
Conclusion Our data do not support prevalence of GST isoenzymes or polymorphisms as a protective effect against PLE. Especially a higher carrier frequency of GSTP1 Val105 as a protective factor against PLE which has been published before could not be proved. The GST genotypes GSTM1, GSTT1 and GSTP1 (including SNPs) seem to have no relevant association with PLE.
Variations in the Glutathione S-transferase (GST) supergene family have been reported to influence cancer susceptibility in Caucasian. However the genetic backgrounds and skin types are quite different between Caucasian and non-Caucasian. We therefore investigated the distribution of GST gene polymorphism in non-Caucasian population to ascertain the role of this polymorphism in skin carcinogenesis. One-hundred and fifteen patients with skin cancers and 92 controls who visited Kobe University Hospital between April 2004 and November 2010 were enrolled in this study. Genotype of GST gene was determined by using polymerase chain reaction-restriction fragments length polymorphism analysis. The frequencies of GSTM1 positive genotype were significantly higher in squamous cell carcinomas than those in controls (adjusted odds ratio = 3.09, 95% confidence interval 1.04 - 9.21). The polymorphism of GSTM1 locus could be an important factor in susceptibility to squamous cell carcinoma among Japanese population.
There is marked interpatient variation in responses to psoralen-ultraviolet A (PUVA) photochemotherapy. Identification of molecular biomarkers of PUVA sensitivity may facilitate treatment predictability.The glutathione S-transferases (GSTs) influence cutaneous defence against UV radiation-induced oxidative stress and are therefore candidate biomarkers of PUVA sensitivity. Several human GSTs, including GSTM1 and GSTT1, are polymorphic, and null polymorphisms have been associated with increased UVB erythemal sensitivity and skin cancer risk. PUVA also increases skin cancer risk.
To investigate the effect of GST genotype on PUVA sensitivity.
We investigated GST genotype in patients starting PUVA (n=111) and the effects of 8-methoxypsoralen (8-MOP) on antioxidant response element (ARE)-regulated gene expression in mammalian cells.
Lower minimal phototoxic doses (MPD) (P=0·022) and higher serum 8-MOP concentrations (P=0·052) were seen in GSTM1-null allele homozygotes compared with patients with one or two active alleles. In a subset of patients with psoriasis (n=50), the GSTM1 genotype was not associated with PUVA outcomes, although MPD [hazard ratio (HR) 1·37; 95% confidence interval (CI) for HR 1·15-1·64] and GSTT1-null (HR 2·39; 95% CI for HR 1·31-4·35) and GSTP1b (HR 1·96; 95% CI for HR 1·10-3·51) genotypes were associated with clearance of psoriasis in this patient group. Exposure of mammalian cells to 8-MOP induced gene expression via the ARE, a regulatory sequence in promoters of cytoprotective genes including GSTs, suggesting that these genes may be implicated in 8-MOP metabolism.
The polymorphic human GSTs are associated with PUVA sensitivity. Further studies are required to examine the clinical relevance of these preliminary findings.
Sick building syndrome (SBS) is a chronic disorder caused by exposure to diverse indoor environmental or chemical pollutants. This study examined the association between seven detoxification genes (CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTP1, and NAT2) and SBS in the Japanese population. One hundred eighty patients with SBS and 401 healthy controls were enrolled in this study. We examined the prevalence for total of eleven genetic polymorphisms of detoxification genes. However, no statistically significant differences in allele and genotype frequency distributions of eleven genetic polymorphisms of these detoxification genes were found between patients and controls. On this basis, we conclude that the polymorphisms that we assessed for the detoxification genes do not contribute to the etiology of SBS.
The incidence of non-melanoma skin cancer (NMSC) is equivalent to that of all other human cancers combined, and genetic factors contribute to risk of the disease. Using genetic crosses of skin tumor promotion sensitive DBA/2 mice with relatively resistant C57BL/6 mice, loci that modify susceptibility to tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) have been mapped to chromosomes (chr) 1, 2, 9, and 19. Here, we show that Glutathione S-transferase alpha 4 (Gsta4), which maps to skin tumor promotion susceptibility locus Psl1.2 on chr 9, was expressed at significantly different levels in the epidermis of C57BL/6 versus DBA/2 mice following treatment with diverse promoting agents. Gsta4 expression was dramatically upregulated in the epidermis of C57BL/6 mice, but not DBA/2 mice, following treatment with TPA, okadaic acid, chrysarobin, or ultraviolet light. Gsta4 deficient mice were more susceptible to skin tumor development in the two-stage skin carcinogenesis protocol providing compelling evidence that Gsta4 underlies the effect of Psl1.2 on susceptibility to skin tumor promotion by TPA. A number of polymorphisms were detected in the putative promoter region of Gsta4 in C57BL/6 versus DBA/2 mice, and ongoing studies are addressing the genetic basis of strain-specific expression of Gsta4 during tumor promotion. Finally, inheritance of polymorphisms in GSTA4 was associated with risk of NMSC in human populations, further supporting Gsta4/GSTA4 as a gene that modifies susceptibility to skin tumor development. Supported by NIH grant ES016623.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4210.
The rising incidence and morbidity of non-melanoma skin cancers has generated great interest in unravelling of their pathogenesis and in the search for new non-invasive treatments. Whereas the role of cumulative sun exposure in pathogenesis of squamous-cell carcinoma seems clear, the relation between sun-exposure patterns and subtypes of basal-cell carcinoma remains undetermined. Several complex genotypic, phenotypic, and environmental factors contribute to pathogenesis of non-melanoma skin cancers. Unlike basal-cell carcinoma, squamous-cell carcinomas can arise from precursor lesions. Diagnosis of non-melanoma skin cancer is made clinically and confirmed by histological testing. Prognosis depends on lesion and host characteristics, which also dictate choice of treatment. Prevention strategies aim at reduction of sun exposure, but are of unproven benefit, especially for basal-cell carcinoma. Surgical excision with predetermined margins is the mainstay of treatment for squamous-cell carcinoma and for most basal-cell carcinomas. Of the new non-invasive treatments, only photodynamic therapy and topical imiquimod have become established treatments for specific subtypes of basal-cell carcinoma, and the search for more effective and tissue-salvaging therapies continues.
Solar radiation can lead to changes affecting DNA metabolism resulting in loss of DNA integrity. Skin specimens obtained from melanoma patients treated at the Memorial Sloan-Kettering Cancer Center were used to study patterns of DNA fragmentation using the comet assay and levels of deletions in mitochondrial DNA (mtDNA) using real-time PCR. Skin specimens were classified according to the glutathione S-transferase M1 (GSTM1) genotype (either wild type [WT] or null) and patient sunburn history. GSTM1 null individuals with a sunburn history showed increased levels of both DNA fragmentation by comet assays and mtDNA deletions relative to GSTM1 WT patients with little or no sunburn history. Microarray analyses identified a number of genes whose expression was upregulated >or=5-fold in cells from GSTM1-null patients or from those reporting histories of sunburn. These genes encoded small molecule transporters, various growth factor/chemokine receptors, transcription factors and tumor suppressors. Of 17 genes directly involved in DNA repair, three DNA ligases were highly upregulated while the RAD23 UV excision repair gene and the Growth Arrest and DNA Damage gene (GADD45) were downregulated. These findings support the idea that exposure to solar radiation early in life may induce long-term cellular changes that lead to persistent DNA damage and altered patterns of gene expression.
Basal cell carcinoma (BCC) is the commonest cancer in Caucasians. Its incidence is rising and many patients develop multiple primary tumours at separate sites. Factors determining time between first primary tumour presentation and the next new primary lesion are unclear. We used Cox's proportional hazards model to study, in 856 Caucasians, the influence of tumour site, individual characteristics and polymorphism in glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYPIAI ) loci on time to next primary tumour presentation. More than one tumour at first presentation (P <0.0001, hazard ratio 2.72) and GSTT1 null (P = 0.028, hazard ratio 1.74) were associated with decreased time to next primary tumour presentation. Significant two-factor interactions, corrected for number of tumours at presentation, were identified between a truncal tumour at first presentation and each of male gender, GSTM1 null and CYP2D6 EM (P <0.003, hazard ratios 3.09-3.82). In each of these cases, all patients with the risk combination demonstrated further separate tumours within 5 years of first presentation. Thus, patients with a truncal tumour at first presentation, especially males and those presenting with more than one lesion have a significantly decreased time to presentation of further tumours and should receive more meticulous follow-up. Polymorphism in GSTM1 and CYP2D6 also influences the rate of new primary tumour accrual giving insights into the link between ultraviolet exposure and multiple tumour development.
The glutathione S-transferase (GST) supergene family comprises gene families that encode isoenzymes that are widely expressed in mammalian tissue cytosols and membranes. Both cytosolic (particularly the isoenzymes encoded by the alpha, mu and theta gene families) and microsomal GST catalyse the conjugation of reduced glutathione (GSH) with a wide variety of electrophiles which include known carcinogens as well as various compounds that are products of oxidative stress including oxidised DNA and lipid. Indeed, several lines of evidence suggest certain of these isoenzymes play a pivotal role in protecting cells from the consequences of such stress. An assessment of the importance of these GST in humans is presently difficult however, because the number of alpha and theta class genes is not known and, the catalytic preferences of even identified isoforms is not always clear.
Cytochrome P450s play a central role in the metabolism and disposition of an extremely wide range of drugs and chemical carcinogens. Individual differences in the expression of these enzymes may be an important determinant in susceptibility to adverse drug reactions, chemical toxins and mutagens. In this paper, we have measured the relative levels of expression of cytochrome P450 isoenzymes from eight gene families or subfamilies in a panel of twelve human liver samples in order to determine the individuality in their expression and whether any forms are co-regulated. Isoenzymes were identified in most cases on Western blots based on the mobility of authentic recombinant human cytochrome P450 standards. The levels of the following P450 proteins correlated with each other: CYP2A6, CYP2B6 and a protein from the CYP2C gene subfamily, CYP2E1 and a member of the CYP2A gene subfamily, CYP2C8, CYP3A3/A4 and total cytochrome P450 content. Also, the levels of two proteins in the CYP4A gene subfamily were highly correlated. These correlations are consistent with the relative regulation of members of these gene families in rats or mice. In addition, the level of expression of specific isoenzymes has also been compared with the rate of metabolism of a panel of drugs, carcinogens and model P450 substrates. These latter studies demonstrate and confirm that the correlations obtained in this manner represent a powerful approach towards the assignment of the metabolism of substrates by specific human P450 isoenzymes.
The purpose of the present study was to determine whether ultraviolet light (UV) irradiation of amino acids produces compounds with affinity for the Ah receptor. Aqueous solutions of L-tryptophan were exposed to radiation from an unfiltered high-pressure mercury lamp. The photoproducts formed were solvent-extracted or concentrated on Sep-Pak C18 cartridges. The concentrated extracts or eluants were treated for their ability to compete with 3H-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Binding was assayed in liver cytosolic preparations from Sprague-Dawley rats using a technique based on hydroxylapatite separation. Photoproducts with receptor affinity were formed in a time-dependent manner. Histidine and tryptamine also gave products upon UV irradiation that competed with TCDD. Commercial tryptophan, at least aged, contained trace amounts of impurities with receptor affinity. Analysis by TLC and high-pressure liquid chromatography of the photo-products of tryptophan showed a minimum of three different binding compounds. Two of the products were studied in greater detail. One of them, showing UV absorbance and yellow fluorescence, gave a molecular ion (M+) of 284 and the other gave M+ 312 but showed little UV absorption and fluorescence. The concentration, based on mass spectrometry quantifications, of the two compounds that displaced more than 50% of TCDD was found to be extremely low, giving Kd values of 0.44 nM (M+ 312) and 0.07 nM (M+ 284). The existence of high affinity receptors for oxidized amino acids is postulated and their possible role in the proliferative cellular responses to TCDD and tryptophan is discussed briefly.
Erythroleukemia K562 cells and lentil (Lens culinaris) root protoplasts have been subjected to pore-forming electric fields suitable for transfection experiments. Evidence is presented that the amount of hydroperoxides formed in cell membranes of both cell-types is a function of field strength applied. On the other hand, the electroporation-induced lipid peroxidation paralleled the enhancement of membrane permeability and was associated with greater membrane fluidity. The membrane hydroperoxides formed upon electric shock enhanced cell luminescence, and lipoxygenase activity appeared to be involved in the process. Electroporation of prokaryotic cells of Escherichia coli also enhanced light emission, which was higher in lipoxygenase-expressing clones.
The glutathione S-transferase (GST) supergene family comprises gene families that encode isoenzymes that are widely expressed in mammalian tissue cytosols and membranes. Both cytosolic (particularly the isoenzymes encoded by the alpha, mu and theta gene families) and microsomal GST catalyse the conjugation of reduced glutathione (GSH) with a wide variety of electrophiles which include known carcinogens as well as various compounds that are products of oxidative stress including oxidised DNA and lipid. Indeed, several lines of evidence suggest certain of these isoenzymes play a pivotal role in protecting cells from the consequences of such stress. An assessment of the importance of these GST in humans is presently difficult however, because the number of alpha and theta class genes is not known and, the catalytic preferences of even identified isoforms is not always clear.
Although basal cell carcinomas and squamous cell carcinomas are clinically and pathologically distinct, the molecular basis for these differences is not clear. We have used polymorphic microsatellite markers to determine the pattern and extent of chromosome losses in a series of 44 basal cell carcinomas and 47 squamous cell neoplasms of the skin. Basal cell carcinomas showed a distinctive allelotype with chromosome loss largely confined to a single chromosome arm, 9q (26 of 44 informative tumors). In contrast to the predominance of loss on a single chromosome arm in basal cell carcinomas, squamous cell neoplasms showed more widespread loss with loss of heterozygosity of markers from 35 of 39 chromosome arms in one or more of the tumors studied. The pattern of loss was also different from basal cell carcinomas with frequent loss of heterozygosity of markers from 9p (41%), 13q (46%), 17p (33%), 17q (33%), and 3p (23%) in squamous cell neoplasms. The frequent loss of markers from these chromosome arms relative to other chromosome losses suggests that these arms may contain genes important in the development of cutaneous squamous cell carcinomas.
The factors that determine development of single and multiple primary cutaneous basal cell carcinomas (BCCs) are unclear. We describe a case-control study firstly, to examine the influence of allelism at the glutathione S-transferase GSTM1 and GSTT1 and cytochrome P450 CYP2D6 loci on susceptibility to these tumours and, secondly, to identify interactions between genotypes and relevant individual characteristics, such as skin type and gender. Frequency distributions for GSTM1 genotypes in cases and controls were not different, although the frequency of GSTM1 A/B was significantly lower (P = 0.048) in the multiple BCCs than in controls. We found no significant differences in the frequencies of GSTT1 and CYP2D6 genotypes in cases and controls. Interactions between genotypes were studied by comparing multinomial frequency distributions in mutually exclusive groups. These identified no differences between cases and controls for combinations of the putatively high risk GSTM1 null, GSTT1 null, CYP2D6 EM genotypes. Interactions between GSTM1 A/B and the CYP2D6 PM and GSTT1-positive genotypes were also not different. Frequency distributions of GSTM1 A/B with CYP2D6 EM in controls and multiple BCCs were significantly different (P = 0.033). The proportion of males in the multiple BCC group (61.3%) was greater than in controls (47.0%) and single BCC (52.2%), and the frequency of the combination GSTM1 null/male gender was significantly greater in patients with multiple tumours (P = 0.002). Frequency distributions of GSTM1 null/skin type 1 were also significantly different (P = 0.029) and the proportion of subjects who were GSTM1 null with skin type 1 was greater (P = 0.009) in the multiple BCC group. We examined the data for interactions between GSTM1 null/skin type 1/male gender by comparing frequency distributions of these factors in the single and multiple BCC groups. The distributions were almost significantly different (exact P = 0.051). No significant interactions between GSTT1 null or CYP2D6 EM and skin type 1 were identified. Comparisons of frequency distributions of smoking with the GSTM1 null, GSTT1 null and CYP2D6 EM genotypes identified no differences between patients with single and multiple tumours.
Allelism in the glutathione S-transferase, GSTM3 gene has been identified using PCR with specific primers to exon 6/exon 7. Sequencing showed the mutant GSTM3*B allele to have a three-base deletion in intron 6 with a frequency of 0.158. The mutation generates a recognition sequence, 5'-AAGATA-3', for the negative transcription factor YY1. GSTM3*B was significantly associated with GSTM1*A.
Objective.-The primary aims of this study were to assess risk of subsequent basal and squamous cell skin cancer among patients with a prior history of these tumors and to examine these risks in relation to patient characteristics and life-style factors. Design.-Follow-up of participants in a randomized trial of betacarotene as a possible skin cancer preventive agent. Setting.-Clinical centers in Los Angeles, Calif, San Francisco, Calif, Minneapolis, Minn, and Hanover, NH. Participants.-Patients (n=1805) who were diagnosed as having a basal or squamous cell skin cancer between January 1980 and February 1986 and were free of skin cancer at study entry. Main Outcome Measure.-Time from study entry to first new occurrence of basal and squamous cell skin cancer. Results.-The estimated risk of developing one or more new skin cancers was 35% at 3 years and 50% at 5 years. New skin cancers tended to be of the same cell type as the previous skin cancers. For both basal and squamous cell skin cancer, risk was higher among patients who were male, were over the age of 60 years, had more prior skin cancers, had severe actinic skin damage, or who burned easily with sun exposure. Compared with those who had never smoked, the rate of subsequent squamous cell skin cancer was higher among current smokers (rate ratio, 2.01; 95% confidence interval, 1.21 to 3.34) and former smokers (rate ratio, 1.62; 95% confidence interval, 1.07 to 2.47) and increased with both duration and amount smoked. There was no clear relationship between smoking and basal cell skin cancer; the rate appeared lower among heavy smokers but was unrelated to duration of smoking. Conclusions.-Persons with a prior nonmelanoma skin cancer had a substantial 5-year risk of developing another tumor of the same histologic type. Number of previous skin.cancers, solar damage, and skin sensitivity to sun exposure were particularly related to this risk. The increased risk of squamous cell skin cancer associated with cigarette smoking merits further study.
Non-melanoma skin cancer patients are believed to be at high risk of developing new skin malignancies; however, relatively few studies have actually examined this. Non-melanoma skin cancers, although generally not fatal, are responsible for significant morbidity and, if left untreated, can causeserious disfigurement and, in rare instances, death. Part of the diffculty in studying these tumors is that they are not routinely followed as rigorously as other cancers, and are excluded from most cancer registries. Prior studies have often included patients from a single dermatology practice or those treated with one type of therapy (e.g., Moh's surgery). Some studies did not entail active follow-up of patients but relied on reports to a registry or subsequent visits initiated by the patient or their physician. Other studies have been based solely on patients with complete follow-up information, excluding those who died or were lost to follow-up. Nearly all studies collected only a limited amount of information on each patient. In an attempt to overcome these limitations, we examined subsequent skin cancer occurrence among a group of patients followed as part of the Skin Cancer Prevention Study. In the following, we highlight some of the methodologic issues concerning the study of subsequent basal cell and squamous cell skin cancer risk, and the contribution of our work, along with that of others, in exploring clinical and etiologic questions pertaining to the occurrence of these malignancies.
A survey of the incidence of non-melanoma skin cancer was undertaken in four areas which included about ten million people. Complete reporting of all newly diagnosed cases of skin cancer which occurred during the survey period of September 1, 1971 to February 29, 1972 was obtained by canvassing dermatologists, radiotherapists, pathologists, and other physicians seeing and treating skin cancer. Rates among Caucasians were found two to three times higher than any ever reported before in these area. An estimate of 300,000 new cases of skin cancer per year would amount to about one-half the total for all other forms of cancer combined in the United States. In all areas, there was an excess liability in males of about 2 to 1. Highest rates were observed in the Dallas-Ft. Worth area, where increased solar radiation is suspected as a carcinogenic agent.
Abstract— An action spectrum for the immediate induction in DNA of single-strand breaks (SSBs, frank breaks plus alkali-labile sites) in human P3 teratoma cells in culture by monochromatic 254-, 270-, 290-, 313-, 334-, 365-, and 405-nm radiation is described. The cells were held at +0.5d̀C during irradiation and were Iysed immediately for alkaline sedimentation analysis following the irradiation treatments. Linear fluence responses were observed over the fluence ranges studied for all energies. Irradiation of the cells in a D2O environment (compared with the normal H2O environment) did not alter the rate of induction of SSBs by 290-nm radiation, whereas the D2O environment enhanced the induction of SSBs by 365- and 405-nm irradiation. Analysis of the relative efficiencies for the induction of SSBs, corrected for quantum efficiency and cellular shielding, revealed a spectrum that coincided closely with nucleic acid absorption below 313 nm. At longer wavelengths, the plot of relative efficiency vs. wavelength contained a minor shoulder in the same wavelength region as that observed in a previously obtained action spectrum for stationary phase Bacillus subtilis cells. Far-UV radiation induced few breaks relative to pyrimidine dimers, whereas in the near-UV region of radiation, SSBs account for a significant proportion of the lesions relative to dimers, with a maximum number of SSBs per lethal event occurring at 365-nm radiation.
We have examined the hypothesis that the polymorphic, glutathione S-transferase GSTP1 gene is a susceptibility candidate for squamous cell cancer of the oral/pharynx and larynx. We describe GSTP1 genotype frequencies in 380 cases and 180 controls. We found a lower frequency of GSTP1 AA in the oral/pharyngeal cases compared with controls (p = 0.003, odds ratio = 0.47) after correction for age and gender. We used an immunohistochemical approach to show widespread expression of the GSTP1 subunit throughout the pharynx and larynx. In uninfiltrated tissue, strong positivity was found throughout the squamous cell epithelium with the exception of the basal cell layer. The cilia of the respiratory epithelium of the larynx also showed positivity for GSTP1. In tumour tissue, expression of GSTP1 was similar in pharyngeal and laryngeal samples. These data are the first to show that polymorphism at GSTP1 mediates susceptibility to squamous cell cancer of the upper aerodigestive tract. No significant interactions were identified between GSTP1 and GSTM1, GSTM3, GSTT1 and the cytochrome P450 CYP1A1, CYP2D6 and CYP1A1 genotypes.
Debrisoquine and its primary metabolite, 4-hydroxydebrisoquine, were measured in the urine of 94 volunteers after a single oral dose of 10 mg debrisoquine. The ratio between excreted debrisoquine and its metabolite was bimorphically distributed in the study population. Family studies supported the view that alicyclic 4-hydroxylation of debrisoquine is controlled by a single autosomal gene and that a defect in this metabolic step is caused by a recessive allele.
The analysis of the repair of damage to DNA in mammalian cells leads not only to a knowledge of which environmental agents are deleterious to living creatures, but also to an understanding of which reaction products in DNA are potentially carcinogenic and which tissues are the more sensitive.
The primary aims of this study were to assess risk of subsequent basal and squamous cell skin cancer among patients with a prior history of these tumors and to examine these risks in relation to patient characteristics and life-style factors.
Follow-up of participants in a randomized trial of betacarotene as a possible skin cancer preventive agent.
Clinical centers in Los Angeles, Calif, San Francisco, Calif, Minneapolis, Minn, and Hanover, NH.
Patients (n = 1805) who were diagnosed as having a basal or squamous cell skin cancer between January 1980 and February 1986 and were free of skin cancer at study entry.
Time from study entry to first new occurrence of basal and squamous cell skin cancer.
The estimated risk of developing one or more new skin cancers was 35% at 3 years and 50% at 5 years. New skin cancers tended to be of the same cell type as the previous skin cancers. For both basal and squamous cell skin cancer, risk was higher among patients who were male, were over the age of 60 years, had more prior skin cancers, had severe actinic skin damage, or who burned easily with sun exposure. Compared with those who had never smoked, the rate of subsequent squamous cell skin cancer was higher among current smokers (rate ratio, 2.01; 95% confidence interval, 1.21 to 3.34) and former smokers (rate ratio, 1.62; 95% confidence interval, 1.07 to 2.47) and increased with both duration and amount smoked. There was no clear relationship between smoking and basal cell skin cancer; the rate appeared lower among heavy smokers but was unrelated to duration of smoking.
Persons with a prior nonmelanoma skin cancer had a substantial 5-year risk of developing another tumor of the same histologic type. Number of previous skin cancers, solar damage, and skin sensitivity to sun exposure were particularly related to this risk. The increased risk of squamous cell skin cancer associated with cigarette smoking merits further study.
A good correlation was observed between enhanced lung cancer risk and restriction fragment length polymorphisms (RFLPs) of the P450IA1 gene with the restriction enzyme MspI. Genotype frequencies of 0.49 for the predominant homozygote, 0.40 for the heterozygote, and 0.11 for the homozygous rare allele were observed in a healthy population. Among lung cancer patients, the frequency of homozygous rare allele of P450IA1 gene was found to be about 3-fold higher than that among healthy population, and this difference was statistically significant. This is the first report to identify the genetically high risk individuals to lung cancer at the gene level.
Individuals with high genetic risk of lung cancer had previously been identified by MspI polymorphisms of the cytochrome P450IA1 gene. In the present study we analyzed the structures of individual P450IA1 genes by PCR direct sequencing of genomic DNA of each genotype raised by the MspI polymorphisms, which were ascribed to a single point mutation in the 3'-flanking region. We then found a novel point mutation in the coding region of the gene which results in the substitution of Ile for Val at residue 462 in the heme binding region. We further analyzed the genetic association between this amino acid replacement and MspI polymorphisms in the general population, using a new method to detect polymorphisms not recognized by restriction enzymes. The results showed that there are at least two forms of human P450IA1 protein with different primary structures and that one of the forms is closely linked with the lung cancer-susceptible genotype of MspI polymorphisms. Thus MspI polymorphisms, which are associated with increased risk of lung cancer, are linked to at least one amino acid substitution, which gives an important clue, at the molecular level, toward elucidation of increased susceptibility to lung cancer.
The glutathione transferases (GSTs) are involved in the metabolism of a wide range of compounds of both exogenous and endogenous origin. There is evidence that deficiency of GST may increase sensitivity to certain environmentally derived carcinogens. In contrast, elevated expression has been implicated in resistance to therapeutic drugs. The GSTs are the products of several gene families. This review summarizes the present knowledge of the genetic interrelationships between the various isoenzymes, their deficiencies and the physical locations of their genes.
The debrisoquine-4-hydroxylase polymorphism is a genetic variation in oxidative drug metabolism characterized by two phenotypes, the extensive metabolizer (EM) and poor metabolizer (PM). Of the Caucasian populations of Europe and North America, 5%-10% are of the PM phenotype and are unable to metabolize debrisoquine and numerous other drugs. The defect is caused by several mutant alleles of the CYP2D6 gene, two of which are detected in about 70% of PMs. We have constructed a genomic library from lymphocyte DNA of an EM positively identified by pedigree analysis to be homozygous for the normal CYP2D6 allele. The normal CYP2D6 gene was isolated; was completely sequenced, including 1,531 and 3,522 bp of 5' and 3' flanking DNA, respectively; and was found to contain nine exons within 4,378 bp. Two other genes, designated CYP2D7 and CYP2D8P, were also cloned and sequenced. CYP2D8P contains several gene-disrupting insertions, deletions, and termination codons within its exons, indicating that this is a pseudogene. CYP2D7, which is just downstream of CYP2D8P, is apparently normal, except for the presence, in the first exon, of an insertion that disrupts the reading frame. A hypothesis is presented that the presence of a pseudogene within the CYP2D subfamily transfers detrimental mutations via gene conversions into the CYP2D6 gene, thus accounting for the high frequency of mutations observed in the CYP2D6 gene in humans.
Superoxide-mediated oxidative stress initiates a chain of events resulting in numerous cellular injuries. We have used genetics and E. coli to investigate the role and regulation of superoxide dismutase (SOD) and its relationship with the other constituents of the oxygen toxicity defence system. Structural SOD genes have been cloned and sequenced, permitting us to refine structural analysis and to isolate SOD-deficient mutants. The conditional oxygen sensitivity of these mutants, together with their increased mutation rate, demonstrated the essential biological role of SOD. Furthermore the complementation of SOD-lacking E. coli deficiencies by introducing a plasmid containing the gene encoding the human SOD supported the proposal that superoxide dismutation is the physiological function of SOD. Regulation of the MnSOD, through which the global SOD level in E. coli is modulated, has been studied using operon and protein fusions with the lactose operon, and led to the conclusion of a multicontrol of MnSOD. Isolation and characterization of regulation mutants are in progress, with the aim of identifying effectors and targets involved in the response to superoxide-mediated oxidative stress.
Constatation d'une deperdition inquietante en ozone stratospherique, mesuree notamment au-dessus de l'Antarctique, depassant de beaucoup les previsions. Facteurs responsables. Consequences previsibles: manque d'absorption des UV, risques accrus de cancer. Autres consequences difficiles a prevoir. Avenir incertain
Free radicals are chemical species characterized by an odd number of orbital electrons or by pairs of electrons of similar directional spin isolated singly in separate orbitals. Consequently most of these agents are highly reactive and usually exhibit an extremely short half-life, although due to steric and resonance effects some exceptions occur. Some radicals and their precursors, such as the diradical O2 which exists in the triplet state, represent a critical and essential element of normal metabolism of aerobic organisms where, under normal circumstances, controlled reduction of reactive oxygen species occurs via the cytochrome oxidase or cytochrome P-450 mixed function monooxygenase systems. In addition to reactive oxygen species, organisms may be subjected to a wide-range of other free radicals or their precursors, including those of both exogenous and endogenous origin. Elaborate defense mechanisms have evolved to avoid cellular damage from these highly reactive species. Enzymes, such as the superoxide dismutase, the glutathione peroxidase/reductase system, and catalase; interactions with conjugated diene systems such as those found in melanins, carotenoids, and tocopherols; and direct reduction by sulphydryl compounds, phenols, and purines represent but a few of these natural defense systems.
A survey of the incidence of non-melanoma skin cancer was undertaken in four areas which included about ten million people. Complete reporting of all newly diagnosed cases of skin cancer which occurred during the survey period of September 1, 1971 to February 29, 1972 was obtained by canvassing dermatologists, radiotherapists, pathologists, and other physicians seeing and treating skin cancer. Rates among Caucasians were found two to three times higher than any ever reported before in these area. An estimate of 300,000 new cases of skin cancer per year would amount to about one-half the total for all other forms of cancer combined in the United States. In all areas, there was an excess liability in males of about 2 to 1. Highest rates were observed in the Dallas-Ft. Worth area, where increased solar radiation is suspected as a carcinogenic agent.
A total of 238 arsenical skin cancers in 153 patients (98 men and 55 women) were histologically studied; 117 patients (76.47%) were older than 50. Of the 238 lesions, 46 were epidermoid carcinoma, 36 basal cell (23 deep and 13 superficial), 139 intraepidermal (18 type B keratoses and 121 classical Bowen's lesions and variants) and 17 combined forms. Clinically, it was often impossible to differentiate superficial basal cell carcinoma, intraepidermal carcinoma and combined forms. Bowen's variants (10 with squamous eddies, 6 with features of seborrheic keratosis and 5 with horn formation) were described and illustrated. The combined forms were mixtures of superficial basal cell carcinoma, Bowen's lesion or its variants and Jadassohn epithelioma, Among the 36 basal cell carcinomas, ten revealed bizarre multinucleated giant cells and nuclear atypicalities, three in deep and seven in superficial. Arsenical keratoses consisted of benign type A and malignant type B (intraepidermal carcinoma). Among the 81 type A keratoses 57 revealed no cell atypicalities and 24 only mild ones. Relationships of Bowen's lesions to keratoses and to invasive and metastasizing carcinomas and of keratoses type A to type B and to epidermoid carcinomas were discussed.
The formation of cyclobutane-type dimers between adjacent pyrimidine residues in model polynucleotides or DNA may be represented by the general scheme
— PyPy′ — hv ⇌ — P ̅y̅P̅y̅′̅ —
whereas the formation of all other known photoproducts follows the irreversible path
— Nucleotide hv → product
Thus dimers are distinguished from other photoproducts by the fact that they can be monomerized, as well as formed, by ultraviolet irradiation. At large incident fluxes of photons the steady-state value of dimers depends on wavelength and p H, as well as on other characteristics of the surrounding medium. The number of dimers in an irradiated polynucleotide may be decreased by purely photochemical means, whereas this is not true for most other photoproducts, for which continued irradiation, irrespective of wavelength, always results in the formation of more photoproduct. The wavelength dependence of the steady-state for dimers is also reflected in the biological activity of irradiated transforming DNA. This experiment and the fact that photoreactivating enzyme plus visible light monomerizes dimers (and has not been demonstrated to have any effect on other photoproducts) are the strongest lines of experimental evidence that pyrimidine dimers of the cyclobutane type are biologically important lesions and can account for a large fraction of the effects of ultraviolet light on DNA in solution. Insofar as DNA is one of the more important biological structures, such dimers, when formed, account for a large part of the effects of ultraviolet radiation on biological systems.
Between the early 1960s and the late 1980s, the incidence of melanoma increased at a rate of 3-7% per year in populations of mainly European origin. Corresponding trends were observed in mortality. Higher rates of increase in incidence were observed in a few populations (eg 8.9% per year in Hawaii whites). With the exception of Japan and possibly Puerto Rico, incidence rates of melanoma have remained stable in the few populations of mainly non-European origin for which reliable incidence data were available. A comparison of age specific trends in incidence and mortality in populations of mainly European origin showed two general patterns: a continuous increase in incidence in all age groups but with moderation or cessation of the previous rising trend in mortality in younger people in more recent time periods (eg Canada, continental USA, Denmark and the UK) and recent moderation or cessation of both incidence and mortality trends in younger people (eg New Zealand and, possibly, Hawaii whites). The first of these two patterns appeared to be the most common. Studies of site specific trends in incidence in 13 populations indicate that the highest rates of increase have generally been for melanomas on the trunk and the lowest for those on the head and neck. There is weak evidence to suggest that the rate of increase on the lower limbs has been greater in women than in men. Studies of incidence trends in the 1980s by thickness of melanoma in seven populations show that relative and absolute incidence has increased most for the thinnest melanomas and least for the thickest lesions. Increasing detection, earlier diagnosis and a real rise may together explain the increase in incidence of melanoma. The increases in mortality suggest that incidence has really increased, and the recent moderation in mortality trends may be explained by improved survival from melanoma due, most likely, to increasingly early diagnosis. In some populations, it may also indicate that the incidence increases are coming to an end. The disproportionately increasing incidence of thin melanoma, the divergence between incidence and mortality trends and the recent sharp increases in incidence in some populations suggest that earlier diagnosis or greater detection of less aggressive melanomas may have contributed to the incidence trends. A progressive change from predominantly occupational to predominantly recreational patterns of sun exposure is the most likely cause of increasing real incidence of melanoma in populations of mainly European origin.
The GSTM1 gene on chromosome lp encodes the carcinogen-detoxification enzyme, glutathione S-transferase (mu subclass). The homozygous
null genotype at this locus has been associated with increased susceptibility to malignancy, including some skin cancers.
One hundred and twenty-four Australian patients with sporadic melanoma and 62 with familial basal cell carcinomas (a feature
of nevoid basal cell carcinoma syndrome, NBCCS) were examined for germline homozygous deletions of GSTM1 using multiplex polymerase chain reactions. The homozygous null genotype was not overrepresented in either those with a single
melanoma or in the NBCCS cases. Nor did it significantly accelerate tumorigenesis in either group. Analyses of much larger
sample sizes will be required to investigate the representation of the null genotype in patients with multiple melanoma primaries
and in those with melanoma coexisting with other non-cutaneous malignancies.
Multiple allelism at loci encoding detoxicating enzymes is associated with cancer risk. We have studied genetic variation at the glutathione S-transferase GSTM1 locus to see whether phenotypes confer altered susceptibility to basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), or multiple skin tumours of different histological types. The frequency of GSTM1 null in cases and controls (52%) was similar, except for patients with two or more tumours of different types (71%, p = 0.033). GSTM1 A/B was reduced in frequency (p < 0.05) in patients with single or multiple BCC. Thus GSTM1 A/B may be protective, and effectiveness of detoxication may be a factor determining susceptibility to skin cancer.
The carcinogenic activity of solar radiation has been known for nearly a century. However, within the past few years, we have realized that exposing the skin to sunlight also has profound immunological effects on the host and that these immunological changes can contribute to the development of skin cancer and alter host resistance to infectious diseases. These findings have led to the development of a new field of research, termed photoimmunology, which is concerned with the effects of UV radiation on immunological processes. Our interest in this field arose from studies on the antigenic properties of skin cancers induced in mice by chronic exposure to UV-B (280-320 nm) radiation. These cancers are highly antigenic and many are immunologically rejected upon transplantation to normal syngeneic recipients. In studying how these cancers were able to survive and grow in the primary host, we discovered that exposing the skin to UV radiation altered some types of immune responses, including the immune response against skin cancers. Studies on the nature and mechanism of the immunological alterations brought about by exposure to UV radiation suggested that UV-induced DNA damage triggers a cascade of events, leading ultimately to a state of antigen-specific, systemic T lymphocyte-mediated immunosuppression. Key components of this cascade are epidermal cytokines, which modulate the immune response to antigens introduced into the UV-irradiated host and divert the response toward a state of specific immunosuppression. The finding that UV radiation can redirect the immune response from an effector to a suppressor pathway has raised the possibility that immune responses to infectious diseases might also be influenced by exposure of the host to UV radiation. Interest in the health consequences of stratospheric ozone depletion, with its attendant increase in solar UV-B radiation, has stimulated recent investigations on the effects of UV radiation on the pathogenesis of infections in animal models and on immune responses in humans. In addition, attempts are being made to use information about UV-induced specific immunosuppression to eliminate unwanted immune responses, such as transplant rejection and graft-versus-host reactions. Thus, studies on the immunological effects of UV radiation are providing new information on how immune responses are regulated as well as improving our understanding of the role of the immune system in skin cancer induction. This information should facilitate the development of more effective measures for preventing the deleterious effects of overexposure to UV radiation.
Molecular genetic analysis is providing us with enormous advances in understanding the pathogenesis of human diseases such as cancer. The study of familial disease and the subsequent mapping and identification of the mutations which contribute to disease susceptibility, is not only providing insights into the factors involved in the pathogenesis of the disease but also identifying new targets for therapy. It is now clear that human tumours result from a complex sequence of mutation events. Each individual step makes the mutated cell more independent of its normal growth regulatory processes, eventually resulting in the formation of a metastatic tumour. There are a multitude of biochemical changes that these mutations confer, which provide preneoplastic cells with a selection advantage. In addition to an increased rate of cell division, such changes may make the cells resistant to cytotoxic insult or to programmed cell death. They can also confer an increased ability to survive independent of a normal hormonal environment. It is now clear that all these types of change may contribute to tumour cell progression.
The factors that determine progression of cervical intra-epithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette smoking is a risk factor, suggesting polymorphism at loci that encode carcinogen-metabolizing enzymes such as glutathione S-transferase (GSTT1, GSTM1) and cytochrome P450 (CYP2D6) may determine susceptibility to these cancers. We have studied the frequency of the null genotype at the theta class GSTT1 locus in women with low-grade CIN, high-grade CIN and SCC. The control group comprised women with normal cervical pathology suffering menorrhagia. We found the frequency of GSTT1 null in the control and case groups was not significantly different, though frequency distributions of combinations of the genotype with smoking in mutually exclusive groups in the high-grade CIN group and the other case groups were significantly different. Interactive effects of GSTT1 null with the GSTM1 null and CYP2D6 EM genotypes, and cigarette smoking were also studied by comparing the multinomial frequency distributions of these factors over mutually exclusive categories. These showed no significant differences between the controls and SCC or low-grade CIN. Frequency distributions in high-grade CIN, however, were significantly different to the controls, and both SCC and low-grade CIN; frequency distributions of GSTT1 null with smoking and CYP2D6 EM, individually and in combination, were significantly different. However, inspection of our data does not indicate that GSTT1 null is a major factor mediating risk. Thus, comparison of chi 2 values for the differences between frequency distributions in high-grade CIN and other groups shows that values for combinations of GSTT1 null with other factors are lower than those for equivalent combinations with smoking and CYP2D6 EM. Interestingly, the combination GSTT1 null/GSTM1 null did not appear to influence susceptibility to CIN or SCC.
Non-melanoma skin cancer patients are believed to be at high risk of developing new skin malignancies; however, relatively few studies have actually examined this. Non-melanoma skin cancers, although generally not fatal, are responsible for significant morbidity and, if left untreated, can cause serious disfigurement and, in rare instances, death. Part of the difficulty in studying these tumors is that they are not routinely followed as rigorously as other cancers, and are excluded from most cancer registries. Prior studies have often included patients from a single dermatology practice of those treated with one type of therapy (e.g., Moh's surgery). Some studies did not entail active follow-up of patients but relied on reports to a registry or subsequent visits initiated by the patient or their physician. Other studies have been based solely on patients with complete follow-up information, excluding those who died or were lost to follow-up. Nearly all studies collected only a limited amount of information on each patient. In an attempt to overcome these limitations, we examined subsequent skin cancer occurrence among a group of patients followed as part of the Skin Cancer Prevention Study. In the following, we highlight some of the methodologic issues concerning the study of subsequent basal cell and squamous cell skin cancer risk, and the contribution of our work, along with that of others, in exploring clinical and etiologic questions pertaining to the occurrence of these malignancies.
Cytochrome P4501A1 (CYP1A1) plays a key role in the metabolic activation of procarcinogenic compounds, leading to skin carcinogenesis. It is therefore important to determine whether its enzymatic activity is altered by topically administered drugs. We investigated, in cultured normal human keratinocytes (NHK), the effects of retinoic acid (RA) and synthetic analogs on the regulation of the CYP1A1 gene. Using transient transfections and gel shift assays, we demonstrated that the human CYP1A1 gene promoter was differentially regulated by retinoid receptors. We report, for the first time, that a RA responsive element 5'-CTTAGGTCACCACGGGGCA-3' (RARE1A1) is present within the promoter region of the CYP1A1 gene.
Non-melanocytic skin cancer has long been regarded as one of the harmful effects of solar ultraviolet (UV) radiation on human health. In this review, we examine epidemiologic evidence linking sun exposure and skin cancer coming from both descriptive studies in populations and analytical studies involving estimates of exposure in individuals. Particular attention is given to the quality of the published data. The epidemiologic evidence that sun exposure causes skin cancer is mainly indirect. Incidence or mortality is inversely related to latitude in populations of mainly European origin (e.g., the United States, Australia), and is higher in people born in Australia (high ambient solar radiation) than in migrants to Australia from the United Kingdom (lower ambient radiation). Skin cancer occurs mainly at sun-exposed body sites and in people who are sensitive to the sun; a reduced capacity to repair UV-induced DNA damage appears to increase the risk. The direct evidence linking sun exposure and skin cancer is weaker with few well-conducted studies of sun exposure in individuals. Mostly, studies of total sun exposure have not found statistically significant positive associations; those that did, had not adjusted for potential confounding by age and gender and thus their interpretation is limited. Studies of occupational sun exposure had relative risks not greater than 2.0; recreational exposure has been little studied. Other measurements, less direct but potentially less prone to measurement error, are sunburn (not evidently associated with skin cancer risk) and indicators of benign cutaneous sun-damage (strongly associated but lacking empirical evidence that sun exposure is their main cause). Many questions remain about the relationship between sun exposure and skin cancer.
We have screened 108 non-small cell lung tumors for mutational alterations in the p53 gene (exons 5 through 8) using polymerase chain reaction and denaturing gel electrophoresis techniques. Thirty-four cases (32%) had aberrant band migrations. The following DNA-sequencing step confirmed the mutations in all these samples. Seventy-six % of the mutations were found at G:C base pairs. Of all the mutations found, 29% were GC to AT, 29% GC to TA, 15% AT to GC, 12% GC to CG, and 3% AT to CG. The other mutations (12%) were deletions or insertions of one base pair. The frequency of p53 mutations among heavy smokers was higher than in nonsmokers (P = 0.047; odds ratio, 6.75; 95% confidence interval, 0.80-57). We examined p53 mutations in relation to genotypes of GSTmu1 and H-ras1. Our data showed that nearly all heavy smokers with transversion mutations were homozygous for the GSTmu1 null allele (10 of 11). The frequency of such mutations was significantly higher for patients with two null alleles (10 of 25) than for those with at least one allele intact (1 of 18) (P = 0.011; odds ratio, 11.33; 95% confidence interval, 1.29-99.3). This study indicated that rare alleles at the variable number of tandem repeats region flanking the H-ras protooncogene are negatively associated to the presence of p53 mutations in the tumors (P = 0.009).
Because death from nonmelanoma skin cancer is uncommon, quantification of its morbidity is particularly important. Although its incidence is increasing rapidly, the most recent nationwide estimates are 16 years old. The purpose of this study was to estimate the 1994 nonmelanoma skin cancer incidence in the United States. We updated the 16-year-old incidence estimates to reflect the growth and changing age distribution of the population and the increases in age-adjusted incidence rates documented in two population-based studies. The projected 1994 incidence of nonmelanoma skin cancer in the United States is 900,000 to 1,200,000 cases, similar in magnitude to the overall incidence of noncutaneous cancers. Nonmelanoma skin cancer imposes an enormous public health burden on the U.S. population. Quantification of its morbidity and its prevention are important priorities.
Defective repair of sunlight-induced DNA photodamage, coupled with an unusually high occurrence of multiple primary basal cell carcinomas (BCCs), is the major characteristic of xeroderma pigmentosum. Our recent work has indicated that this etiological paradigm may apply to skin cancer patients without an apparent hereditary disease. The present study reports on an investigation of whether medications such as photosensitizing drugs (antibiotics, corticosteroids, and aspirin) modulate skin cancer risk through alterations in DNA repair capacity (DRC). Using a new DNA repair (host cell reactivation) assay with peripheral T-lymphocytes, we tested DRCs of 88 Caucasian BCC patients and 135 cancer-free controls. Subjects were between 20 and 60 years of age and free of known hereditary skin diseases. The age-adjusted means of DRC were calculated to compare repair levels associated with the use of specific drugs and hormones. Multiple linear regression models were used to correlate DRC with the number of skin cancers. The estimated odds ratio was used to describe the risk of BCCs. The distribution of DRCs of subjects was approximately normal, with a 5-fold variation between individuals. DRCs below the upper 30th percentile of controls were associated with an estimated 2.3-fold (95% confidence interval, 1.17-4.54-fold) increased risk for the occurrence of BCCs. The lower the DRC was, the greater the number of skin tumors in individuals (P < 0.05), after adjustment for age. Although supplemental vitamin use was associated with reduced risk of skin cancer, it was not associated with differences in subjects' DRCs. However, individuals who reported taking either tetracycline or estrogen, two photosensitizing drugs, had higher DRCs, compared with those who had not used these drugs. Low DRC or a family history of skin cancer increased the probability that patients who were overexposed to sunlight would have multiple BCCs. DNA repair levels may be influenced by the use of selected photosensitizing drugs and estrogen.
Genes encoding many of the so-called drug-metabolizing enzymes (DMEs) are present in both prokaryotes and eukaryotes, suggesting that these genes arose on this planet more than 3.5 billion years ago--long before animal-plant divergence (estimated to be about 1.2 billion years ago) and long before the use and commercial development of drugs. What, therefore, are the real functions of DMEs? Several years ago I proposed that DMEs are upstream in the regulatory cascade of numerous signal transduction pathways, i.e. necessary for maintaining physiologically "safe", or "acceptable", steady-state levels of all small non-protein endogenous ligands (M(r) = 250 +/- 200) in each cell. Innumerable foreign chemicals and drugs mimic these small endogenous ligands, thus binding to a particular receptor and acting either as an agonist or antagonist in activating or inhibiting genes effecting growth, differentiation, apoptosis, homeostasis and neuroendocrine functions. Discussed in this review are additional examples consistent with this theory and not described in previous reviews, including: (i) insect-plant symbiosis; (ii) "cross-talk" amongst genes in the aromatic hydrocarbon-responsive [Ah] battery; (iii) signal transduction pathways involving the arachidonic acid cascade; and (iv) the explanation in carcinogen-screening studies as to why a maximum, or half maximum, tolerated dose (MTD, MTD50) of many test compounds might cause cell division and tumorigenesis in experimental animals.
Glutathione S-transferases (GSTs) are a group of enzymes which play an important role in the detoxication of xenobiotics. It is shown that the expression of human glutathione S-transferase P1-1 (GSTP1-1) is suppressed by retinoic acid (RA) as the result of decreased transcription from its gene, GSTP1. Chloramphenicol acetyltransferase (CAT) assays indicate that the effect of RA on the transcription of a GSTP1 promoter-CAT fusion gene is mediated by the region -99 to +72 of GSTP1. A consensus activator protein 1-binding site, located at nucleotide position -59 to -65 of GSTP1, is suggested to be responsible for RA repression. This effect of RA on GSTP1 expression is mediated by the human beta-type RA receptor, hRAR beta, but not the chicken retinoid X receptor, cRXR. The retinoid X receptor does not augment the action of hRAR beta on GSTP1. In addition, it is shown that GSTP1-1 expression is enhanced by insulin as a result of increased transcription of GSTP1. Assay of CAT activity indicates that the effect of insulin on the transcription of GSTP1 is also mediated by the region -99 to +72 of GSTP1. Comparison with sequences of other insulin-responsive genes, suggests that insulin enhancement of GSTP1 expression is effected by an eight-base-pair sequence, 'CCCGCGTC', located at +48 to +55 in intron 1 of the gene. These results are discussed in relation to the increased expression of GSTP1-1 in many tumour cells.
Using a combination of somatic cell hybrids, in situ hybridization, and linkage mapping, we have been able to localize the cytochrome P450 CYP2D6 gene to chromosome 22 in the region q13.1. Linkage analysis, using locus-specific primers, showed a maximum sex-average lod score of 8.12 (theta = 0.00) between the marker pH130 (D22S64) and CYP2D6, of 6.92 (theta = 0.00) between the marker KI839 (D22S95) and CYP2D6, and of 4.80 (theta = 0.036) between the platelet-derived growth factor beta subunit gene (PDGFB) and CYP2D6.