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Source publication
In this paper, we present evidence that alleles of several polymorphisms in the chromosomal region 19q13.2-3, encompassing the genes RAI and XPD, are associated with occurrence of basal cell carcinoma in Caucasian Americans. The association of one of these, RAI-intron1, is sufficiently strong to make mass significance unlikely (P = 0.004, chi(2))....
Context in source publication
Context 1
... surprisingly, the two markers were in linkage disequilibrium, and the protective alleles were correlated. Table 5 lists the frequencies of the rare alleles in controls and in all cases as well as in young cases (50 years at onset). It is quite clear that the RAI intron 1 G allele is underrepresented in the cases, and there are suggestions that several of the neighboring SNP variants also differ in frequency between cases and controls. ...
Citations
... 2-19q13.4. Over the years, genetic markers in that region have been associated with many different types of cancer susceptibility, including breast cancer Yin et al., 2002;Nexo et al., 2003Nexo et al., , 2008Vogel et al., 2004;Amin Al Olama et al., 2013;Gao et al., 2018). Nonetheless, inherited mutations in CEACAM genes have yet to be associated with inherited risk of cancer (Zheng et al., 2011;Kammerer et al., 2012;Wang et al., 2015). ...
Introduction
Recent studies comparing canine mammary tumors (CMTs) and human breast cancers have revealed remarkable tumor similarities, identifying shared expression profiles and acquired mutations. CMTs can also provide a model of inherited breast cancer susceptibility in humans; thus, we investigated breed-specific whole genome sequencing (WGS) data in search for novel CMT risk factors that could subsequently explain inherited breast cancer risk in humans.
Methods
WGS was carried out on five CMT-affected Gold Retrievers from a large pedigree of 18 CMT-affected dogs. Protein truncating variants (PTVs) detected in all five samples (within human orthlogs) were validated and then genotyped in the 13 remaining CMT-affected Golden Retrievers. Allele frequencies were compared to canine controls. Subsequently, human blood-derived exomes from The Cancer Genome Atlas breast cancer cases were analyzed and allele frequencies were compared to Exome Variant Server ethnic-matched controls.
Results
Carcinoembryonic Antigen-related Cell Adhesion Molecule 24 (CEACAM24) c.247dupG;p.(Val83Glyfs∗48) was the only validated variant and had a frequency of 66.7% amongst the 18 Golden Retrievers with CMT. This was significant compared to the European Variation Archive (p-value 1.52 × 10–8) and non-Golden Retriever American Kennel Club breeds (p-value 2.48 × 10–5). With no direct ortholog of CEACAM24 in humans but high homology to all CEACAM gene family proteins, all human CEACAM genes were investigated for PTVs. A total of six and sixteen rare PTVs were identified in African and European American breast cancer cases, respectively. Single variant assessment revealed five PTVs associated with breast cancer risk. Gene-based aggregation analyses revealed that rare PTVs in CEACAM6, CEACAM7, and CEACAM8 are associated with European American breast cancer risk, and rare PTVs in CEACAM7 are associated with breast cancer risk in African Americans. Ultimately, rare PTVs in the entire CEACAM gene family are associated with breast cancer risk in both European and African Americans with respective p-values of 1.75 × 10–13 and 1.87 × 10–04.
Conclusion
This study reports the first association of inherited CEACAM mutations and breast cancer risk, and potentially implicates the whole gene family in genetic risk. Precisely how these mutations contribute to breast cancer needs to be determined; especially considering our current knowledge on the role that the CEACAM gene family plays in tumor development, progression, and metastasis.
... The 751 Gln variant maybe is an innocent bystander! XPD, ERCC1 and RAI2 genes are encoded at 19q13.2-3 and certain haplotypic blocks of these genes are associated with risk of development of basal cell carcinoma [34] and breast cancer [35] and also lung cancer prognosis and development [36]. Banescu et al. show that XPD 751 Gln variant is associated with increased risk of development of AML in a case-control study (OR: 2.55; 95% CI: 1.53-4.25; ...
Aim: Acute myeloid leukemia (AML) is a heterogeneous disease in pathogenesis and response to therapy. Nucleotide excision repair (NER) pathway has a major role in the elimination of genotoxic effects of chemotherapeutic agents. We aimed to clarify the effects of selected variants of XPD, XPC, ERCC5 and ERCC1 genes on the outcomes of induction therapy. Materials & methods: The prevalence of NER genetic variants was evaluated in 67 subjects with AML and their effects on clinical outcomes were analyzed by χ ² test. Results: The XPD 751 Lys variant was associated with improved response to chemotherapy compared with XPD 751 Gln and Lys/Gln variants (p = 0.023; odds ratio: 4.5; 95% CI: 1.14–17.73). There were no associations between other genotypes and any outcomes. Conclusion: Current findings suggest that XPD Lys751Gln variant could be considered as a prognostic factor in AML.
... Several studies [11][12][13][14][15] were also performed on association between SNPs within NER gene and NMSC risks, but the limited number for these articles could not concluded a consistent result on this association, and could not clarify the mechanism between NER gene and NMSC susceptibility. Some studies support a non-significantly association between these variants and decreased risk of NMSC [14,22], whereas others have found non-significant increases in NMSC risk [11,23]. Previously, just one study [15] has reported evidence on the association between either rs2228527 or rs2228529 and NMSC, a thorough evaluation of NER gene variants revealed associations between two functional ERCC6 SNPs and NMSC, which to our knowledge have been reported firstly, and the increased risk was consistent among both men and women. ...
Aims
To investigate the association of several single nucleotide polymorphisms (SNPs) within nucleotide excision repair (NER) gene and additional gene- gene and gene- smoking interaction with non-melanoma skin cancer (NMSC) risk in a Chinese population.
Methods
A total of 1322 participants (939 males, 383 females) were selected, including 660 NMSC patients and 662 control participants. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and smoking. Logistic regression was performed to investigate association between 4 SNPs within NER gene, additional gene- gene and gene- smoking interaction on NMSC risk.
Results
NMSC risk was significantly higher in carriers with G allele of rs2228527 than those with AA genotype (AG + GG versus AA), adjusted OR (95%CI) =1.76 (1.24-2.37), and higher in carriers with the G allele of rs2228529 than those with AA genotype (AG + GG versus AA), adjusted OR (95%CI) = 1.66 (1.24-2.13). However, we did not find any direct association of the rs4134822 and rs1799793 with NMSC risk after covariates adjustment. GMDR model indicated a significant interaction combination (p=0.0010), including rs2228529 and current smoking. Overall, the cross-validation consistency of this model was 9/ 10, and the testing accuracy was 60.72%. Current smokers with rs2228529- GA or GG genotype have the highest NMSC risk, compared to never- smokers with rs2228529- AA genotype, OR (95%CI) = 2.92 (1.61-4.29).
Conclusions
We found that the G allele of rs2228527 and the G allele of rs2228529 within NER gene, interaction between rs2228529 and current smoking were all associated with increased NMSC risk.
... Figure 1 shows the selection process of this meta-analysis. The 10 articles included were conducted in 10 different countries: UK, 29 Denmark, 30,31 USA, 32 Sweden/Finland, 33 Sweden, 34 Korea, 35 Japan, 36 Germany, 37 and Taiwan (China). 38 Three were conducted in Asian populations and seven in Caucasian populations. ...
Objective
Non-melanoma skin cancer (NMSC) is the most common malignancy with annually rising incidence. The aim of this study was to estimate the association between three coding polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) of the DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) and NMSC susceptibility.
Methods
Online databases were searched to retrieve case–control studies published between January 2000 and November 2016. Pooled odds ratio (OR) and 95% confidence interval (CI) were employed to assess the strength of association. Overall, 10 relevant studies were finally included for analysis, including 3,143 NMSC patients and 3,540 controls. For each polymorphism of XRCC1 gene, there were 3,050 cases and 3,463 controls for Arg399Gln, 914 cases and 1,182 controls for Arg194Trp, and 279 cases and 413 controls for Arg280His.
Results
Our results showed that these three polymorphisms in the XRCC1 coding region were not associated with increased risk of NMSC in the total studied population. However, subgroup analysis by ethnicities demonstrated that Gln/Arg genotype of Arg399Gln polymorphism was associated with increased risk of NMSC under the heterogeneous model in Asian populations (Gln/Arg vs Arg/Arg: OR =1.39, 95% CI =1.04–1.87, P=0.03); subgroup analysis by tumor types showed that Trp/Trp genotype of Arg194Trp was positively associated with decreased cancer risk in squamous-cell skin cancer (SCC) type under the homogeneous model (Trp/Trp vs Arg/Arg: OR =0.38, 95% CI =0.16–0.92, P=0.03).
Conclusion
Our results suggested that Arg399Gln variant of XRCC1 gene might be a risk factor for NMSC in Asian populations, and Arg194Trp variant of XRCC1 gene might be a protective factor for patients with SCC. In addition, future case–control studies are still needed to further evaluate the effect of XRCC1 polymorphisms in NMSC risk.
... Three linkage disequilibrium (LD)-mapping studies in Caucasian populations have identified the subregion encompassing ERCC2, PPP1R13L, CD3EAP and ERCC1 within chromosome 19q13.3 as being associated with risk of basal cell carcinoma, breast cancer and with multiple myeloma prognosis [4,5,1,6]. Fine-mapping of cancer susceptibility related to the four genes at this chromosome region is still pending in Asian populations. Since the allele frequencies of a number of polymorphisms are very different among Caucasians and Asians, finemapping of the region in Asians may provide a tool for identification of the causal genetic variants. ...
Linkage disequilibrium-mapping studies in Caucasians have indicated anassociation of Chr19q13.3 sub-region spanning ERCC2, PPP1R13L, CD3EAP and ERCC1 with several cancers. To refine the region of association and identify potential causal variations among Asians, we performed a fine-mapping study using 32 (39) SNPs in a 71.654kb sub-region. The study included 384 Chinese lung cancer cases and 387 controls. Seven closely situated SNPs showed significant associations with lung cancer risk in five different genetic models of single-locus associations (adjusted for smoking duration). These were PPP1R13L rs1970764 [OR (95% CI) = 1.58 (1.09-2.29), P = 0.014] in a recessive model and PPP1R13L rs1005165 [OR (95% CI) = 1.25 (1.01-1.54), P = 0.036], CD3EAP rs967591 [OR (95% CI) = 1.40 (1.13-1.75), P = 0.0023], rs735482 [OR (95% CI) = 1.29 (1.03-1.61), P = 0.026], rs1007616 [OR (95% CI) = 0.78 (0.61-1.00), P = 0.046], and rs62109563 [OR (95% CI) = 1.28 (1.03-1.59), P = 0.024] in a log-additive model and ERCC1 rs3212965 [OR (95% CI) = 0.70 (0.52-0.94), P = 0.019] in an over-dominant model. Six-haplotype blocks were determined in the sub-region. Using an alternative approach where we performed a haplotype analysis of all significant polymorphisms, rs1970764 was found to be most consistently associated with lung cancer risk. The combined data suggest that the sub-region with the strongest association to lung cancer susceptibility might locate to the 23.173kb from PPP1R13L intron8 rs1970764 to rs62109563 3' to CD3EAP. Limited risk loci and span on lung cancer in this sub-region are initially defined among Asians.
... Previous studies have demonstrated a relationship between the risk of developing cancer and polymorphisms located in this region [16][17][18][19]. Moreover, it was reported that the overlapping genes ERCC1, CD3EAP, and PPP1R13L may interact in apoptosis and DNA repair pathways [16,17,20,21]. PPP1R13L is an inhibitor of p53 that primarily affects apoptosis [22]. ...
Objectives
Individual variations in the capacity of DNA repair machinery to relieve benzene-induced DNA damage may be the key to developing chronic benzene poisoning (CBP), an increasingly prevalent occupational disease in China. ERCC1 (Excision repair cross complementation group 1) is located on chromosome 19q13.2–3 and participates in the crucial steps of Nucleotide Excision Repair (NER); moreover, we determined that one of its polymorphisms, ERCC1 rs11615, is a biomarker for CBP susceptibility in our previous report. Our aim is to further explore the deeper association between some genetic variations related to ERCC1 polymorphisms and CBP risk.
Methods
Nine single nucleotide polymorphisms (SNPs) of XRCC1 (X-ray repair cross-complementing 1), CD3EAP (CD3e molecule, epsilon associated protein), PPP1R13L (protein phosphatase 1, regulatory subunit 13 like), XPB (Xeroderma pigmentosum group B), XPC (Xeroderma pigmentosum group C) and XPF (Xeroderma pigmentosum group F) were genotyped by the Snapshot and TaqMan-MGB® probe techniques, in a study involving 102 CBP patients and 204 controls. The potential interactions between these SNPs and lifestyle factors, such as smoking and drinking, were assessed using a stratified analysis.
Results
An XRCC1 allele, rs25487, was related to a higher risk of CBP (P<0.001) even after stratifying for potential confounders. Carriers of the TT genotype of XRCC1 rs1799782 who were alcohol drinkers (OR = 8.000; 95% CI: 1.316–48.645; P = 0.022), male (OR = 9.333; 95% CI: 1.593–54.672; P = 0.019), and had an exposure of ≤12 years (OR = 2.612; 95% CI: 1.048–6.510; P = 0.035) had an increased risk of CBP. However, the T allele in PPP1R13L rs1005165 (P<0.05) and the GA allele in CD3EAP rs967591 (OR = 0.162; 95% CI: 0039~0.666; P = 0.037) decreased the risk of CBP in men. The haplotype analysis of XRCC1 indicated that XRCC1 rs25487A, rs25489G and rs1799782T (OR = 15.469; 95% CI: 5.536–43.225; P<0.001) were associated with a high risk of CBP.
Conclusions
The findings showed that the rs25487 and rs1799782 polymorphisms of XRCC1 may contribute to an individual’s susceptibility to CBP and may be used as valid biomarkers. Overall, the genes on chromosome 19q13.2–3 may have a special significance in the development of CBP in occupationally exposed Chinese populations.
... It has been reported that haplotypes of 3 single-nucleotide polymorphisms (SNP), rs1970764T>C (PPP1R13L IVS8-1435), rs967591G>A (-8358 from PPP1R13L, or -21 from CD3EAP), and rs11615G>A (ERCC1 N118N), are associated with the risk of basal cell carcinoma, breast cancer, and lung cancer (12)(13)(14) suggesting that genetic variation(s) in the 19q13.3 region may affect the susceptibility to cancer. ...
Purpose:
This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) in 19q13.3 and survival of patients with early-stage non-small cell lung cancer (NSCLC), and to define the causative functional SNP of the association.
Experimental design:
A two-stage study design was used to evaluate five SNPs in relation to survival outcomes in 328 patients and then to validate the results in an independent patient population (n = 483). Luciferase assay and real-time PCR were conducted to examine functional relevance of a potentially functional SNP.
Results:
Of the five SNPs, three SNPs (rs105165C>T, rs967591G>A, and rs735482A>C) were significantly associated with survival outcomes in a stage I study. The rs967591A allele had significantly higher activity of the CD3EAP promoter compared with the rs967591G allele (P = 0.002), but the SNP did not have an effect on the activity of PPP1R13L promoter. The rs967591G>A was associated with the level of CD3EAP mRNA expression in lung tissues (P = 0.01). The rs967591G>A exhibited consistent associations in a stage II study. In combined analysis, the rs967591 AA genotype exhibited a worse overall survival (adjusted HR = 1.69; 95% confidence interval = 1.29-2.20; P = 0.0001).
Conclusion:
The rs967591G>A affects CD3EAP expression and thus influences survival in early-stage NSCLC. The analysis of the rs967591G>A polymorphism can help identify patients at high risk of a poor disease outcome.
... It thus stands to reason that more common, but less penetrant NER gene variants may be associated with NMSC risk in the general population. Studies of polymorphisms in NER genes have examined their association with NMSC risk, with inconsistent findings (Applebaum et al. 2007; Vogel et al. 2001; Vogel et al. 2005; Yin et al. 2002; Han et al. 2005; Lovatt et al. 2005; Miller et al. 2006; Dybdahl et al. 1999). Many of these focused on only two or three genes, and only functional single nucleotide polymorphisms (SNPs), that is, instances where variation in a single base pair in the DNA results in a different amino acid upon translation. ...
... Due to a low genotyping platform design score, rs1799793 was not genotyped. Many studies have measured the association between these three XPD and XPA polymorphisms and NMSC (Applebaum et al. 2007; Vogel et al. 2001; Vogel et al. 2005; Yin et al. 2002; Han et al. 2005; Lovatt et al. 2005; Miller et al. 2006; Dybdahl et al. 1999). The largest of these, drawing from a population-based study in New Hampshire with nearly 900 cases of BCC and 700 of SCC, observed a 15–25% decreased risk of either BCC or SCC among those with the XPA A23G (rs1800975) polymorphism (Miller et al. 2006), as well as a 20% decreased risk of SCC and 10% decreased risk of BCC among those carrying variant forms of both XPD Lys751Gln and Asp312Asn (Applebaum et al. 2007), after adjusting for age, sex, skin pigmentation, and number of severe sunburns. ...
... There was a significant 30–40% reduced risk of SCC among carriers of the XPD Lys751Gln (rs13181) variant in the Nurses Health Study (n = 286 SCC cases, n = 874 controls), and a roughly 20% decreased risk for XPD Asp312Asn (rs1799793), while neither was associated with BCC (n = 300 cases), adjusting for age, race, skin type, sunburns, family history, geography, tanning bed use, and sun exposures (Han et al. 2005 ). Some studies support a nonsignificantly decreased risk of NMSC associated with these variants (Vogel et al. 2005; Lovatt et al. 2005), while others have found non-significant increases in risk (Vogel et al. 2001; Vogel et al. 2005; Yin et al. 2002). In general, more of the NER SNPs associated with NMSC were associated with BCC than SCC, adding supportive evidence for the hypothesis that risk of BCC and SCC may be associated with different NER genes and pathophysiology. ...
Nucleotide excision repair (NER) is responsible for protecting DNA in skin cells against ultraviolet radiation-induced damage. Using a candidate pathway approach, a matched case-control study nested within a prospective, community-based cohort was carried out to test the hypothesis that single nucleotide polymorphisms (SNPs) in NER genes are associated with susceptibility to non-melanoma skin cancer (NMSC). Histologically-confirmed cases of NMSC (n=900) were matched to controls (n=900) on age, gender, and skin type. Associations were measured between NMSC and 221 SNPs in 26 NER genes. Using the additive model, two tightly linked functional SNPs in ERCC6 were significantly associated with increased risk of NMSC: rs2228527 (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.20 - 2.05), and rs2228529 (OR 1.57, 95% CI 1.20 - 2.05). These associations were confined to basal cell carcinoma of the skin (BCC) (rs2228529, OR 1.78, 95% CI 1.30 - 2.44; rs2228527 OR 1.78, 95% CI 1.31 - 2.43). These novel, hypothesis-generating findings suggest functional variants in ERCC6 may be associated with an increased risk of NMSC that may be specific to BCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2639. doi:1538-7445.AM2012-2639
... In addition, 39 controls were matched on gender and age. The distribution of genotypes in the controls of all studies was consistent with HWE except for six studies (33,35,45,47,49,53), which were tested using sensitivity analyses. Two studies used the same control group (32,50), so they were grouped as one in the meta-analyses of all subjects with exception of those stratified by cancer type. ...
Individual studies of the associations between excision repair cross-complimentary group 1 (ERCC1) polymorphisms and cancer susceptibility have shown inconclusive results. To derive a more precise estimation of the relationship between three well-characterised polymorphisms on ERCC1 and the risk of cancer, we performed a meta-analysis based on 48 publications. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the associations. We found that ERCC1 17677A (rs3212961) variant genotypes were associated with significantly increased overall risk of cancer without substantial heterogeneity (AA versus CC, OR = 1.36, 95% CIs: 1.10-1.68; AC versus CC: OR = 1.11, 95% CIs: 0.99-1.26; dominant comparison: AA/AC versus CC: OR = 1.15, 95% CIs: 1.02-1.29; recessive comparison: AA versus AC/CC: OR = 1.25, 95% CIs: 1.05-1.49). The ERCC1 19007 C (rs11615) allele had null effects on overall risk of cancer; but in the stratified analyses, we observed an elevated association in Asian populations with homozygote variants and hospital-based controls. In addition, during further stratified analyses of cancer groups, homozygote variants were found that are associated with lung cancer and smoking-related cancers. Also, the observed ERCC1 19007 C heterozygote variant contributes to the development of skin cancer. However, the ERCC1 8092C > A (rs3212986) polymorphism did not appear to have an effect on cancer risk. Additionally, no evidence of publication bias was observed in these polymorphisms. Our meta-analysis supports the conclusion that the ERCC1 17677A > C and ERCC1 19007T > C polymorphisms, but not the ERCC1 8092C > A polymorphism, are low-penetrance risk factors for cancer development.
... This exceptional type of gene overlap was conserved in mouse and even in the yeast ERCC1 homolog, RAD10, suggesting an important biologic function of this region (19q13.2-q13.3). Besides, haplotypes in this region have been found associated with increased cancer risk [61][62][63][64][65]. Although we have found an association between MPM and a XRCC1 haplotype and a cumulative of XRCC1 and ERCC1 variants, we have not observed an association with ERCC1 haplotypes. ...
Malignant pleural mesothelioma (MPM) is a rare aggressive tumor associated with asbestos exposure. The possible role of genetic factors has also been suggested and MPM has been associated with single nucleotide polymorphisms (SNPs) of xenobiotic and oxidative metabolism enzymes. We have identified an association of the DNA repair gene XRCC1 with MPM in the population of Casale Monferrato, a town exposed to high asbestos pollution. To extend this observation we examined 35 SNPs in 15 genes that could be involved in MPM carcinogenicity in 220 MPM patients and 296 controls from two case-control studies conducted in Casale (151 patients, 252 controls) and Turin (69 patients, 44 controls), respectively. Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Two DNA repair genes were associated with MPM, i.e. XRCC1 and ERCC1. Considering asbestos-exposed only, the risk increased with the increasing number of XRCC1-399Q alleles (Casale: OR=1.44, 95%CI 1.02-2.03; Casale+Turin: OR=1.34, 95%CI 0.98-1.84) or XRCC1 -77T alleles (Casale+Turin: OR=1.33, 95%CI 0.97-1.81). The XRCC1-TGGGGGAACAGA haplotype was significantly associated with MPM (Casale: OR=1.76, 95%CI 1.04-2.96). Patients heterozygotes for ERCC1 N118N showed an increased OR in all subjects (OR=1.66, 95%CI 1.06-2.60) and in asbestos-exposed only (OR=1.59, 95%CI 1.01-2.50). When the dominant model was considered (i.e. ERCC1 heterozygotes CT plus homozygotes CC versus homozygotes TT) the risk was statistically significant both in all subjects (OR=1.61, 95%CI 1.06-2.47) and in asbestos-exposed only (OR=1.56, 95%CI 1.02-2.40). The combination of ERCC1 N118N and XRCC1 R399Q was statistically significant (Casale: OR=2.02, 95%CI 1.01-4.05; Casale+Turin: OR=2.39, 95%CI 1.29-4.43). The association of MPM with DNA repair genes support the hypothesis that an increased susceptibility to DNA damage may favour asbestos carcinogenicity.
