Fig 4 - uploaded by Saima Shakil Malik
Content may be subject to copyright.
Kaplan-Meier estimates representing association of XPC polymorphisms with OS and PFS in BC cases. a, b No association of rs2228001 polymorphism with PFS and OS among BC cases. c, d No
Source publication
Background:
Gene polymorphisms that affect nucleotide excision repair (NER) pathway may link with higher susceptibility of breast cancer (BC); however, the significance of these associations may vary conferring to the individual ethnicity. Xeroderma pigmentosum complementation gene (XPC) plays a substantial role in recognizing damaged DNA during N...
Context in source publication
Context 1
... of XPC polymorphisms with OS and PFS was measured among BC cases with the help of Kaplan-Meier Survival curve (Fig. 4) and Cox proportional hazards model, respectively. Even though heterozygous genotypes of both polymorphisms (rs2733532 and rs2228001) were associated with BC risk, they exhibited no association (P ≥ 0.05) with OS and PFS (Table 3). Though noticeable differences were observed among wild type and altered genotypes of rs2733532 with PFS, ...
Citations
... The sample size was calculated with the formula provided {n = Zα /2 2 pq/(MOE) 2 } using the frequency of BC from the literature as 12-15%. Therefore, applying an estimated population size of 15% with a margin of error of 5%, the calculated sample size was 195, 20 where Zα /2 is a statistical constant, p is the prevalence, and MOE is the margin of error or relative precision. Sampling was carried out after taking written informed consent from both patients and controls. ...
... The phenol-chloroform extraction method was employed for the genomic DNA extraction from peripheral blood samples. 20 Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR) was utilized for the genotyping of CYP2C19*2, CYP2C19*3, and CYP2C19*17 by allele-specific polymerase chain reaction (AS-PCR). The sequences of primers are given in Table 1. ...
Breast cancer (BC) continues to be the most common cancer in the women worldwide. Since estrogen receptor (ER)-positive BC accounts for the majority of newly diagnosed cases, endocrine therapy is advised to utilize either tamoxifen (Tam) or aromatase inhibitors. The use of Tam as a monotherapy or in conjunction with an aromatase inhibitor following two or three years of endocrine therapy has long been recommended. When used adjuvantly, Tam medication reduces BC mortality and relapses, while it extends survival times in metastatic BC when used in conjunction with other treatments. Unfortunately, the efficiency of Tam varies considerably. This study was conducted to explore the influence of genetic polymorphisms in CYP2C19 gene on Tam's pharmacogenetics and pharmacokinetics in estrogen-positive BC patients. Data from healthy, unrelated individuals (n = 410; control group) and ER-positive BC patients (n = 430) receiving 20 mg of Tam per day were recruited. Steady-state plasma concentrations of Tam and its three metabolites were quantified using the high-performance liquid chromatography in the patients. The CYP2C19 polymorphisms were genotyped using an Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) approach. More than 65% of healthy individuals were extensive metabolizers (*1/*1) for CYP2C19, whereas more than 70% of ER-positive BC patients were rapid and ultrarapid metabolizers (*1/17*, *17/17*). The polymorphism CYP2C19*17 is significantly associated with higher 4-hydroxytamoxifen (4-OH-Tam). Patients with the *17/*17 genotype exhibited 1- to 1.5-fold higher 4-OH-Tam, which was also high in patients with the *1/*2 and *2/*2 genotypes.
... Polymorphisms in the ERCC1 and XPC genes may influence the genomic stability then [45]. And Malik et al. suggested that rs2228001 A > C may change the Cterminus functional preferences and structure of XPC, then contribute to the breast cancer risk [46]. However, no study reports the association between the SNP in NER pathway genes and AR susceptibility. ...
Background:
Allergic rhinitis (AR) is the most frequent inflammatory disorder in the nasal mucosa that remains unclear etiology. Mounting studies suggested that genetic instability could trigger and worsen the inflammatory response. The nucleotide excision repair (NER) system is an important pathway in maintaining the stability of the genome. Therefore, the genetic variations in NER pathway genes may have potential effects on AR risk.
Methods:
We evaluated the correlation between 19 candidate single nucleotide polymorphisms (SNPs) in NER pathway genes and AR susceptibility by a case-control study in a Chinese population, which contains 508 AR cases and 526 controls.
Results:
Three independent SNPs were identified as significantly associated with AR susceptibility, including ERCC1 rs2298881 C > A (recessive model: adjusted odds ratios (OR) = 0.30, 95%confidence interval (CI) = 0.18-0.50, P < 0.0001), ERCC1 rs11615 G > A (dominant model: adjusted OR = 1.44, 95%CI = 1.04-2.01, P = 0.030), and XPC rs2228001 A > C (dominant model: adjusted OR = 0.68, 95%CI = 0.49-0.95, P = 0.024). Stratified analysis showed that ERCC1 rs2298881 AA genotype was correlated with a lower risk of AR among all the subgroups compared with rs2298881 CC/CA genotype. XPC rs2228001 AC/CC genotype reduced AR risk among the following subgroups: age > 60 months, clinical stage I and III.
Conclusion:
Our finding showed that genetic variations in NER pathway genes: ERCC1 and XPC may affect the risk of AR, which will provide new insights into the genetics of AR from the perspective of DNA damage repair.
... The XPC polymorphism Ala499Val was found to play a protective role in developing advanced colorectal adenomas in smokers (105), and others have suggested a protective role of higher XPC mRNA and protein expression levels on colorectal survival, possibly related to an improved response to chemoradiation (106). A recent casecontrol association study using tissue from 493 breast cancer and 387 control cases suggested an association between two XPC polymorphisms, rs2228001-A>C (Lys939Gln) and rs2733532-C>T, with an increased odds of breast cancer (107), and another study with 200 cases and controls suggested an association between the XPC PAT+ allele and higher odds of breast cancer (108). ...
Xeroderma pigmentosum complementation group C (XPC) is a DNA damage recognition protein essential for initiation of global-genomic nucleotide excision repair (GG-NER). Humans carrying germline mutations in the XPC gene exhibit strong susceptibility to skin cancer due to defective removal via GG-NER of genotoxic, solar UV-induced dipyrimidine photoproducts. However, XPC is increasingly recognized as important for protection against non-dermatologic cancers, not only through its role in GG-NER, but also by participating in other DNA repair pathways, in the DNA damage response and in transcriptional regulation. Additionally, XPC expression levels and polymorphisms likely impact development and may serve as predictive and therapeutic biomarkers in a number of these non-dermatologic cancers. Here we review the existing literature, focusing on the role of XPC in non-dermatologic cancer development, progression, and treatment response, and highlight possible future applications of XPC as a prognostic and therapeutic biomarker.
... It counteracts the harmful effects caused by mutagenic exposure of cells by recognizing the lesion, protein binding, excision of oligonucleotides and reconstruction of DNA fragment. NER pathway comprises of more than thirty proteins and among them seven are xeroderma pigmentosum (XP) complementation groups (ranging from XPA to XPG) representing malfunctioning proteins [5,6]. ...
XPG protein is a crucial component of the nucleotide excision repair pathway. Various single nucleotide polymorphisms of XPG gene have been reported to modulate colorectal cancer susceptibility. Therefore, this case control study evaluated the association of XPG (rs1 047 768 T>C) polymorphism with risk of colorectal cancer. In this study total 175 individuals comprising of age matched one hundred pathologically confirmed colorectal cancer cases and seventy-five controls were genotyped for XPG (rs1 047 768 T>C) polymorphism. Genotyping was accomplished with “Tetra amplification-refractory mutation system (ARMS) PCR” and PCR products were electrophoretically resolved on agarose gel. To validate the results 10% samples were re-analysed for XPG genotyping. Demographic factors were represented by mean ± SD. Multivariate logistic regression analysis was applied to compute odds ratio and confidence interval considering association between genotypes, demographic factors and colorectal cancer risk. Results were computed by MedCalc and SPSS version 24. Results showed significant association of XPG rs1 047 768—T>C genotype (OR: 7.51, CI: 1.63–35.02) and increased risk of colorectal cancer. Additionally, smoking and family history were significant contributors in colorectal cancer development. In summary, XPG (rs1 047 768 T>C) polymorphism is a low susceptibility penetrance gene for colorectal cancer and has never been screened before in Pakistani population.
... Being genetically predisposed or having a family history of a first-degree relative with breast ca was shown to increase the cancer incidence [2][3][4]. Parental marriage to a relative was also shown to increase the risk [5]. Among women aged 40 years or more, breast ca is related to increased risk [6,7]. ...
Background:
Early age at menarche, late age at menopause, and late age at first full-term pregnancy are linked to a modest increase in the risk of developing breast cancer (breast ca). This study aims to investigate the reproductive determinants of breast cancer among women in the West Bank of Palestine. A structured questionnaire was used to collect data in a case-control study (237 registered cases and 237 controls). A multivariate analysis model was used to adjust for the association between women's reproductive factors and breast ca risk. This study was approved by Al Quds University Ethical Research Committee and the Ministry of Health research unit.
Results:
In the multivariate analysis, menarche after 13 years of age, use of oral contraceptives for more than two months, and hormonal contraceptives use significantly doubled the risk for breast ca (Adjusted Odds Ratio (AOR) = 2.03, 95 % CI: 1.21-4.37, p < 0.011 and AOR = 2.2, 95 % CI: 1.24-4.01, p = 0.008, respectively). Women who used hormone replacement therapy (HRT) were significantly associated with higher odds (5 folds) of having breast ca versus those who did not use them (AOR 5.02, 95 % CI: 1.93-13.06, p = 0.001). Similarly, nulliparous women showed 6 times the odds of breast ca compared with women with one or more children (p = 0.005). Also, parental consanguinity marriage (AOR 2.59, 95 % CI: 1.53-4.36, p = 0.001) and positive family history (AOR 3.88, 95 % CI: 2.19-6.87, p = 0.001) of the condition can be strong determinants for breast ca in this study.
Conclusion:
This study provides clear evidence that the use of reproductive hormones, whether as a birth control tool or for therapeutic purposes, must be rationalized worldwide and in Palestine in particular.
... Global cancer burden 2017 attributed the variations in BC incident rates to population growth and aging process [32]. Various other studies have also supported the findings that being a complex chronic systemic disease, BC likely to have significant association with age, as disease incidence increases with increased age [33][34][35][36][37]. Decreased deaths and DALYs among developed countries were attributed to the adoption of widespread mammographic screening of the disease [15,33]. ...
Introduction
Breast cancer (BC) is the most widely studied disease due to its higher prevalence, heterogeneity and mortality.
Objectives
This study aimed to compare female BC trends among 21 world regions and globally over 28 year of data and to assess the association between sociodemographic transitions and female BC risks.
Methods
We used Global burden of disease study data and measure the female BC burden according to 21 world regions and sociodemographic indices (SDI). Age-period-cohort (APC) analysis was used to estimate time and cohort trend of BC in different SDI regions.
Results
By world regions, age-standardised rate of female BC incidence were high in high-income-North America (ASR, 92.9; (95%UI, 89.2, 96.6)), Western Europe (84.7; (73.4, 97.2)) and Australia (86; (81.7, 90.2)) in 2017. Whereas this rate was significantly increased by 89.5% between 1990 and 2017 in East Asia. We observed negative association between SDI and death, and DALYs in 25th and below percentiles of death and DALYs of worldwide regions. Further, there was observed a strong negative correlation between SDI and case fatality percent (r2017= -0.93; r1990= -0.92) in both 2017 and 1990 worldwide and highest case fatality percentage was observed in Central Sub-Saharan Africa. Overall, the risk of case-fatality rate tends to decrease most noticeably in high middle SDI countries, and the reduction of the risk of case-fatality rate in the recent cohort was the lowest in the low SDI countries.
Conclusions
Remarkable variations exist among various regions in BC burden. There is a need to reduce the health burden from BC in less developed and under developing countries, because under-developed countries are facing higher degree of health-related burden. Public health managers should execute more classified and cost-effective screening and treatment interferences to lessen the deaths caused by BC, predominantly among middle and low SDI countries having inadequate healthcare supplies.
... ERCC1 and XPA increase the risk of breast cancer [37,38]. XPC polymorphisms are associated with higher susceptibility of breast cancer during the nucleotide excision repair (NER) process [39]. We also found seven DNA repair genes-BLM, BRCA2, MSH2, XRCC2, RAD51, CHEK1, and CHEK2-that were positively associated with tumor mutation load and neoantigen expression. ...
Simple Summary
Neoantigens are novel proteins presented on the cell surface and derived from the accumulation of somatic mutations in tumor cells. They can be recognized by the immune system and may play a crucial role in boosting immune responses against tumor cells. The impact of neoantigen expression and T-cell activation status on overall survival was investigated in a breast cancer cohort. We found that high neoantigen expression and T-cell activation status was correlated with improved patient survival in the study population. This result supports that neoantigens are promising to serve as immunogenic agents for immunotherapy in breast cancer.
Abstract
Neoantigens are derived from tumor-specific somatic mutations. Neoantigen-based synthesized peptides have been under clinical investigation to boost cancer immunotherapy efficacy. The promising results prompt us to further elucidate the effect of neoantigen expression on patient survival in breast cancer. We applied Kaplan–Meier survival and multivariable Cox regression models to evaluate the effect of neoantigen expression and its interaction with T-cell activation on overall survival in a cohort of 729 breast cancer patients. Pearson’s chi-squared tests were used to assess the relationships between neoantigen expression and clinical pathological variables. Spearman correlation analysis was conducted to identify correlations between neoantigen expression, mutation load, and DNA repair gene expression. ERCC1, XPA, and XPC were negatively associated with neoantigen expression, while BLM, BRCA2, MSH2, XRCC2, RAD51, CHEK1, and CHEK2 were positively associated with neoantigen expression. Based on the multivariable Cox proportional hazard model, patients with a high level of neoantigen expression and activated T-cell status showed improved overall survival. Similarly, in the T-cell exhaustion and progesterone receptor (PR) positive subgroups, patients with a high level of neoantigen expression showed prolonged survival. In contrast, there was no significant difference in the T-cell activation and PR negative subgroups. In conclusion, neoantigens may serve as immunogenic agents for immunotherapy in breast cancer.
... On the contrary, these results can help us predict whether a smoker or betel quid chewer has a higher risk for oral cancer. An increased risk has also been seen in several types of cancers, including breast (33,34), lung (35), bladder (11,36), colorectal (37), prostate (38), gastric cancer (39) in various populations. Notably, the role of XPC in oral cancer is still lacking, and we are the first to investigate its expression levels of mRNA and protein. ...
Background/aim:
Xeroderma pigmentosum complementation group C (XPC) is reported to play important roles in DNA integrity and genomic instability, however, the contribution of XPC to oral carcinogenesis is largely uncertain. Therefore, we aimed at examining the contribution of XPC genotypes to oral cancer.
Materials and methods:
The genotypes of XPC rs2228001 and rs2228000 were examined among 958 oral cancer patients and 958 control subjects by polymerase chain reaction-restriction fragment length polymorphism methodology and corresponding DNA repair capacity was checked.
Results:
First, the percentages of XPC rs2228001 AC and CC were higher among oral cancer patients than controls. Second, no significant association was observed regarding XPC rs2228000. Third, there was a synergistic influence of smoking and betel quid chewing behaviors and XPC rs2228001 genotype on oral cancer risk. Last, functional experiments showed DNA repair capacity was lower for AC/CC carriers than AA carriers.
Conclusion:
XPC rs2228001 C allele, which was associated with decreased DNA repair capacity, may interact with smoking and betel quid chewing behaviors on oral cancer risk.
... Being genetically predisposed or having a family history of rst degree relative with breast ca was shown to increase the cancer incidence [2][3][4][5][6]. Also, parental marriage, which is marriage from a relative, was shown to increase the risk too [7,8]. Among women aged 40 years or more, breast ca is related to an increased risk [9,10]. ...
Background: Early age at menarche, late age at menopause, and late age at first full-term pregnancy are linked to a modest increase in the risk of developing breast cancer (breast ca). Multiparity is related to an increased risk but multiple full-term pregnancies decrease the risk of breast cancers. This study aims to investigate the reproductive determinants of breast cancer among women in the West Bank of Palestine.
Methods: A structured questionnaire was used to collect data in a case-control study; 237 registered cases and 237 controls aged 40 years old or more. A multivariate analysis model was used to adjust for the association between women’s reproductive factors and breast ca risk. Adjusted odds ratio (AOR) and 95% confidence interval (95% CI) are reported. This study was approved by Al Quds University Ethical Research Committee and the Ministry of Health research unit. All women provided written informed consent.
Results: In the multivariate analysis, having menarche after 13 years of age, using oral contraceptives for more than two months, using hormone replacement therapy (HRT), and getting pregnant at an early age (≤18 years) significantly doubled the risk for breast ca. Women who used hormonal contraceptives were significantly associated with higher odds of having breast ca 6.37 compared to those who did not use them (p <0.05). Similarly, nulliparous women showed 6 times the odds of breast ca be compared with women with one or more children (p = 0.005). Also, the mother’s educational level; parental consanguinity marriage; and positive family history of breast ca be strong determinants for breast ca in this study.
Conclusions: This study provides clear evidence of the role of using oral contraceptives and hormonal replacement therapy on women's breasts ca. Therefore, reproductive hormones use, whether as a birth control tool or in therapy, must be rationalized. More in-depth investigations are needed to identify the protective role of having children and breastfeeding practices on breast ca protection. Special attention should be considered for the special social and cultural factors related to sexual and reproductive issues among women in Palestine
Xeroderma pigmentosum C (XPC) is a key initiator in the global genome nucleotide excision repair pathway in mammalian cells. Inherited mutations in the XPC gene can cause xeroderma pigmentosum (XP) cancer predisposition syndrome that dramatically increases the susceptibility to sunlight-induced cancers. Various genetic variants and mutations of the protein have been reported in cancer databases and literature. The current lack of a high-resolution 3-D structure of human XPC makes it difficult to assess the structural impact of the mutations/genetic variations. Using the available high-resolution crystal structure of its yeast ortholog, Rad4, we built a homology model of human XPC protein and compared it with a model generated by AlphaFold. The two models are largely consistent with each other in the structured domains. We have also assessed the degree of conservation for each residue using 966 sequences of XPC orthologs. Our structure- and sequence conservation-based assessments largely agree with the variant’s impact on the protein’s structural stability, computed by FoldX and SDM. Known XP missense mutations such as Y585C, W690S, and C771Y are consistently predicted to destabilize the protein’s structure. Our analyses also reveal several highly conserved hydrophobic regions that are surface-exposed, which may indicate novel intermolecular interfaces that are yet to be characterized.
Communicated by Ramaswamy H. Sarma
