Gene Summary

Gene:ERCC5; ERCC excision repair 5, endonuclease
Aliases: XPG, UVDR, XPGC, COFS3, ERCM2, ERCC5-201
Summary:This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA repair protein complementing XP-G cells
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ERCC5 (cancer-related)

Avci H, Iplik ES, Aydemir L, et al.
Are XPD and XPG gene variants related to the mechanism of oral squamous cell carcinoma?
Cell Mol Biol (Noisy-le-grand). 2018; 64(15):94-99 [PubMed] Related Publications
Oral cavity cancers have anatomically a big part of the body system and include several types of cancer. The aim of the study is to investigate the relation between XPG and XPD gene variants in the DNA repair system and oral squamous cell cancers. A total of 111 patients with a pathologic diagnosis of oral squamous cell carcinoma and a control group of 148 healthy volunteers who presented to Istanbul Faculty of Medicine, Department of Otolaryngology & Head and Neck Surgery and Dentistry Faculty were included in the study. Isolation of DNA was achieved using an Invitrogen Purelink Genomic DNA Kit. XPD alleles of Lys751Gln (rs13181) and XPG Asp1104His (rs17655) loci from genomic DNA samples were reproduced using polymerase chain reaction. A statistically significant difference in XPD genotype distribution between control and patient groups was determined (P=0.019). XPD Lys+ was significantly more common in the patient group than in the control group, and a two-fold increased risk for disease was determined. XPD Gln/Gln+ was significantly more common in the control group than in the patient group, and a two-fold decrease in risk for disease was determined (P=0.045). In the other region of the study, there was no statistically significant difference in terms of disease development between XPG genotypes. In conclusion, Lys751Gln polymorphism in the XPD gene could play a role in oral squamous cell development. It is important to increase the numbers of subjects in patient groups and healthy controls in studies to increase the possibility of determining XPD's potential as a molecular risk factor.

Li T, Ling H, Lu Y, et al.
Meta-analysis of the relationship between excision repair cross-complementing Group 5 rs17655 gene polymorphism and head and neck cancer susceptibility.
J Cancer Res Ther. 2018; 14(Supplement):S1041-S1047 [PubMed] Related Publications
Background: Published studies have evaluated the association between excision repair cross-complementing Group 5 (ERCC5) rs17655 polymorphism and head and neck cancer (HNC) susceptibility. However, these studies showed inconsistent results.
Aims: The aim of this study was to get a more comprehensive estimation of this association.
Materials and Methods: Multiple databases were searched for the genetic association on the ERCC5 rs17655 polymorphism and HNC risk. Ten studies with a total of 3922 cases and 5871 controls were finally identified to be eligible studies in this meta-analysis. Odds ratio with 95% confidence intervals was used to assess the strength of association.
Results: Overall, this meta-analysis showed that there was no association between ERCC5 rs17655 polymorphism and HNC risk under all five genetic models. Further, no significant associations between the ERCC5 rs17655 polymorphism and HNC risk were found under the five genetic models in subgroup analyses based on the source of control. However, in stratified analyses by ethnicity, a significant association was found under the homozygous and recessive models in European.
Conclusions: Our investigations demonstrate that genotypes for the ERCC5 rs17655 polymorphism may be not associated with overall cancer risk. In a subgroup meta-analysis, the results suggest that the ERCC5 rs17655 polymorphism is probably associated with HNC risk in European, but the results should be interpreted with caution for the low number of studies.

Kong J, Liu Z, Cai F, et al.
Relationship between the Asp1104His polymorphism of the nucleotide excision repair gene ERCC5 and treatment sensitivity to oxaliplatin in patients with advanced colorectal cancer in China.
Clinics (Sao Paulo). 2018; 73:e455 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To study the relationship between the Asp1104His polymorphism of the nucleotide excision repair gene ERCC5 and treatment sensitivity to oxaliplatin in patients with advanced colorectal cancer (CRC) in China.
METHODS: A group of 226 patients in the Department of Gastrointestinal Oncology at Zhejiang Xiaoshan Hospital from July 2011∼December 2016 and a control group of 226 normal healthy individuals were involved in this study. All patients were first diagnosed with advanced CRC and were treated with oxaliplatin-based chemotherapy. The genotype of ERCC5 at the site of amino acid 1104 was determined by a TaqMan probe-based real-time PCR approach.
RESULTS: There were no differences in age or gender between the groups, but the percentages of smokers and individuals with a family history of cancer were significantly higher in the patient group than in the control group. Analysis of the G/C polymorphism frequency among the patients and the healthy controls showed that the frequencies of the CC genotype and the CC+GC genotype were significantly related to CRC, but no significant difference in these frequencies was found between genders. The analysis of the relationship between the 5-year survival rate and different genotypes showed that in the total patient group, regardless of gender, the 5-year survival rate was significantly associated with the Asp1104His polymorphism of ERCC5.
CONCLUSIONS: The Asp1104His polymorphism of ERCC5 was associated with the risk and 5-year survival rate of CRC as well as treatment sensitivity to oxaliplatin.

Bonache S, Esteban I, Moles-Fernández A, et al.
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.
J Cancer Res Clin Oncol. 2018; 144(12):2495-2513 [PubMed] Related Publications
PURPOSE: Few and small studies have been reported about multigene testing usage by massively parallel sequencing in European cancer families. There is an open debate about what genes should be tested, and the actionability of some included genes is under research.
METHODS: We investigated a panel of 34 known high/moderate-risk cancer genes, including 16 related to breast or ovarian cancer (BC/OC) genes, and 63 candidate genes to BC/OC in 192 clinically suspicious of hereditary breast/ovarian cancer (HBOC) Spanish families without pathogenic variants in BRCA1 or BRCA2 (BRCA1/2).
RESULTS: We identified 16 patients who carried a high- or moderate-risk pathogenic variant in eight genes: 4 PALB2, 3 ATM, 2 RAD51D, 2 TP53, 2 APC, 1 BRIP1, 1 PTEN and 1 PMS2. These findings led to increased surveillance or prevention options in 12 patients and predictive testing in their family members. We detected 383 unique variants of uncertain significance in known cancer genes, of which 35 were prioritized in silico. Eighteen loss-of-function variants were detected in candidate BC/OC genes in 17 patients (1 BARD1, 1 ERCC3, 1 ERCC5, 2 FANCE, 1 FANCI, 2 FANCL, 1 FANCM, 1 MCPH1, 1 PPM1D, 2 RBBP8, 3 RECQL4 and 1 with SLX4 and XRCC2), three of which also carry pathogenic variants in known cancer genes.
CONCLUSIONS: Eight percent of the BRCA1/2 negative patients carry pathogenic variants in other actionable genes. The multigene panel usage improves the diagnostic yield in HBOC testing and it is an effective tool to identify potentially new candidate genes.

Merriman JD, Sereika SM, Conley YP, et al.
Exploratory Study of Associations Between DNA Repair and Oxidative Stress Gene Polymorphisms and Cognitive Problems Reported by Postmenopausal Women With and Without Breast Cancer.
Biol Res Nurs. 2019; 21(1):50-60 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
PURPOSE: Women with breast cancer report varying frequencies of cognitive problems during adjuvant systemic therapy. This variability suggests latent subgroups. Therefore, we identified latent subgroups of self-reported cognitive problems among postmenopausal women with and without breast cancer. We explored associations between membership in these subgroups and (a) demographic, clinical, and symptom characteristics and (b) variations in candidate gene polymorphisms.
METHODS: We evaluated frequency of cognitive problems using the Patient Assessment of Own Functioning Inventory. Growth mixture modeling identified latent subgroups over 18 months of adjuvant systemic therapy and at matched time points for women without cancer ( N = 331). We evaluated for differences among subgroups in demographic, clinical, and symptom characteristics and in 41 single nucleotide polymorphisms in 10 candidate genes involved in DNA repair and oxidative stress pathways ( n = 199). We modeled associations between genotypes and subgroup membership using multinomial logistic regression.
RESULTS: We identified three latent subgroups: more frequent, persistent, and almost never. Receipt of chemotherapy plus anastrozole, depressive symptoms, and baseline neuropathic symptoms increased the odds of belonging to the more frequent subgroup. Anxiety and depressive symptoms increased the odds of belonging to the persistent subgroup. With covariates controlled for, carrying the ERCC5 rs873601 G minor allele increased the odds of reporting more frequent cognitive problems.
CONCLUSIONS: Chemotherapy plus anastrozole, depressive symptoms, and presence of neuropathic symptoms may predict more frequent cognitive problems during systemic therapy that later resolve. Mood dysregulation before therapy may predict persistent cognitive problems during therapy. ERCC5 genotype may influence frequency of cognitive problems after controlling for these risk factors.

Liu ZQ, Chen GG, Sun RL, et al.
Biosci Rep. 2018; 38(5) [PubMed] Article available free on PMC after 01/01/2020 Related Publications

Zhang R, Zhou F, Cheng L, et al.
Genetic variants in nucleotide excision repair pathway predict survival of esophageal squamous cell cancer patients receiving platinum-based chemotherapy.
Mol Carcinog. 2018; 57(11):1553-1565 [PubMed] Related Publications
The benefits of platinum-based chemotherapy (PBC) on survival of esophageal squamous cell carcinoma (ESCC) patients are inexplicit due to the varied therapeutic effects. Nucleotide excision repair (NER) pathway plays a vital role in removing platinum-DNA adducts in tumor cells and hence may modulate the therapeutic effect and survival outcome. The present study assessed the associations of 26 potentially functional regulatory single nucleotide polymorphisms (rSNPs) in nine core NER genes with disease-free survival (DFS) and overall survival (OS) in 339 ESCC patients. We found that ERCC2 rs2097215 T and rs3916788 A, ERCC5 rs3759497 A and XPC rs3731054 C alleles were associated with unfavorable DFS. Patients carrying high-risk allele group (HRG, 5-8 risk alleles) had a significantly shorter DFS, compared with those carrying low-risk alleles (LRG, 0-4 risk alleles) [adjusted hazards ratio (HR

Zhao J, Chen S, Zhou H, et al.
Aging (Albany NY). 2018; 10(5):1073-1088 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Xeroderma pigmentosum group G (XPG), a key component in nucleotide excision repair pathway, functions to cut DNA lesions during DNA repair. Genetic variations that alter DNA repair gene expression or function may decrease DNA repair ability and impair genome integrity, thereby predisposing to cancer. The association between

Zhang Z, Yin J, Xu Q, Shi J
Association between the XPG gene rs2094258 polymorphism and risk of gastric cancer.
J Clin Lab Anal. 2018; 32(8):e22564 [PubMed] Related Publications
BACKGROUND: Xeroderma pigmentosum group G (XPG) plays an important role in maintaining the stability and integrity of genomic DNA. Previous studies demonstrate some XPG gene polymorphisms are associated with susceptibility to gastric cancer (GC).
METHODS: The association between XPG rs2094258 polymorphism and GC risk was investigated first by a hospital-based case-control study involving 386 patients and 439 controls and then by a meta-analysis. The polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLR).
RESULTS: Xeroderma pigmentosum group G rs2094258 polymorphism was associated with an increased risk of GC in a Chinese population. The meta-analysis did not reveal any significant difference in the overall population. Subgroup analysis of geographic locations showed a significant association between the XPG gene rs2094258 polymorphism and GC risk in Southern China. Stratification analysis further indicated significant associations in hospital-based studies and studies using PCR-RFLR.
CONCLUSION: Xeroderma pigmentosum group G gene rs2094258 polymorphism may be associated with an increased risk of GC in Southern China. Nevertheless, the findings of this meta-analysis should be validated by well-designed large-scale case-control studies among other ethnicities.

Zhao Z, Zhang A, Zhao Y, et al.
The association of polymorphisms in nucleotide excision repair genes with ovarian cancer susceptibility.
Biosci Rep. 2018; 38(3) [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Nucleotide excision repair (NER), the core mechanism of DNA repair pathway, was commonly used to maintain genomic stability and prevent tumorigenesis. Previous investigations have demonstrated that single nucleotide polymorphisms (SNPs) of NER pathway genes were associated with various types of cancer. However, there was no research elucidating the genetic association of entire NER pathway with ovarian cancer susceptibility. Therefore, we conducted genotyping for 17 SNPs of six NER core genes (

Liu J, Li H, Sun L, et al.
The Differential Expression of Core Genes in Nucleotide Excision Repair Pathway Indicates Colorectal Carcinogenesis and Prognosis.
Biomed Res Int. 2018; 2018:9651320 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Background: Nucleotide excision repair (NER) plays a critical role in maintaining genome integrity. This study aimed to investigate the expression of NER genes and their associations with colorectal cancer (CRC) development.
Method: Expressions of NER genes in CRC and normal tissues were analysed by ONCOMINE. The Cancer Genome Atlas (TCGA) data were downloaded to explore relationship of NER expression with clinicopathological parameters and survival of CRC.
Results: ERCC1, ERCC2, ERCC5, and DDB2 were upregulated while ERCC4 was downregulated in CRC. For colon cancer, high ERCC3 expression was related to better T stage; ERCC5 expression indicated deeper T stage and distant metastasis; DDB2 expression suggested earlier TNM stage. For rectal cancer, ERCC2 expression correlated with favourable T stage; XPA expression predicted worse TNM stage. ERCC2 expression was associated with worse overall survival (OS) in colon cancer (HR = 1.53,
Conclusion: ERCC1, ERCC2, ERCC4, ERCC5, and DDB2 were differently expressed in CRC and normal tissues; ERCC2, ERCC3, ERCC5, XPA, and DDB2 correlated with clinicopathological parameters of CRC, while ERCC2, ERCC4, and XPC might predict CRC prognosis.

Sang L, Lv Z, Sun LP, et al.
Impact of SNP-SNP interactions of DNA repair gene
World J Gastroenterol. 2018; 24(5):602-612 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
AIM: To investigate the interactions of the DNA repair gene excision repair cross complementing group 5 (
RESULTS: Two pairwise combinations (
CONCLUSION: There is a multifarious interaction between the DNA repair gene

Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, et al.
Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer.
Pathol Res Pract. 2018; 214(1):44-52 [PubMed] Related Publications
Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC. No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.

Kindil Z, Senhaji MA, Bakhchane A, et al.
Genetic investigation of XPA gene: high frequency of the c.682C>T mutation in Moroccan XP patients with moderate clinical profile.
BMC Res Notes. 2017; 10(1):704 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
OBJECTIVE: Xeroderma pigmentosum (XP) is a genetically and clinically heterogeneous disease, associated with an inherited defect in one of eight different genes (XPA to XPG and XPV). In addition to the early onset of the skin manifestations, the XP group A is marked by the presence of a mild to severe neural disorders which appear tardily and worsens with age. In this study, 9 patients with moderate clinical profile belonging to 6 XP families were recruited to determine the XPA mutational spectrum in Morocco, using the direct sequencing of the whole coding region of the XPA gene.
RESULTS: The genetic investigation of the XPA gene showed that 7 from 9 patients were homozygous for the c.682C>T, p.Arg228X mutation, while all their investigated family members were heterozygous. The frequency of this mutation was estimated to be 83.33% (5/6 families) .The molecular analysis of the 5 other exons of the XPA gene, showed that the 2 negative siblings carried no mutation in the XPA gene. This finding suggests that c.682C>T (p.Arg228X) mutation is relatively associated with moderate phenotype in XP group A Moroccan families; this result will also contribute to improve the molecular diagnosis of XP disease in Moroccan patients.

Liang J, Xu YY, Zhang C, Xia QR
Association of XPG gene rs751402 polymorphism with gastric cancer risk: a meta-analysis in the Chinese population.
Int J Biol Markers. 2018; 33(2):174-179 [PubMed] Related Publications
BACKGROUND: Previous studies have revealed a conflicting relationship of xeroderma pigmentosum group G (XPG) gene polymorphism with gastric cancer (GC) risk. To our knowledge, this is the first meta-analysis to investigate the association between rs751402 mutation located on the XPG promoter region and GC risk.
METHODS: We undertook a meta-analysis by identifying relevant articles from the PubMed, Web of Science and China National Knowledge Infrastructure (CNKI) databases on February 28, 2017. By pooling 9 eligible studies, 3,539 GC cases and 3,948 controls were included. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using the fixed-effects or random-effects model depending on the existence of heterogeneity across studies. The population attributable risk (PAR%) was estimated to better understand the public health risk.
RESULTS: All included studies had been conducted in China. Significant associations were found between the XPG rs751402 polymorphism and the risk of GC (TT vs. CC: OR = 1.43, 95% CI, 1.11-1.84; CT vs. CC: OR = 1.15, 95% CI, 1.04-1.26; dominant model: OR = 1.17, 95% CI, 1.07-1.29; recessive model: OR = 1.30, 95% CI, 1.05-1.62; T vs. C: OR = 1.18, 95% CI, 1.06-1.32). The estimated PAR% was about 4.9%-8.8%. Funnel plots did not reveal any potential publication bias. The sensitivity analyses showed that the results were relatively robust.
CONCLUSIONS: This meta-analysis indicates that the XPG rs751402 polymorphism may be a risk factor for GC in the Chinese population.

Shah K, Mehmood S, Jan A, et al.
Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families.
Int J Dermatol. 2017; 56(12):1406-1413 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study.
METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families.
RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes.
CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.

Musich PR, Li Z, Zou Y
Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation.
Adv Exp Med Biol. 2017; 996:41-54 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The sensitivity of Xeroderma pigmentosa (XP) patients to sunlight has spurred the discovery and genetic and biochemical analysis of the eight XP gene products (XPA-XPG plus XPV) responsible for this disorder. These studies also have served to elucidate the nucleotide excision repair (NER) process, especially the critical role played by the XPA protein. More recent studies have shown that NER also involves numerous other proteins normally employed in DNA metabolism and cell cycle regulation. Central among these is ataxia telangiectasia and Rad3-related (ATR), a protein kinase involved in intracellular signaling in response to DNA damage, especially DNA damage-induced replicative stresses. This review summarizes recent findings on the interplay between ATR as a DNA damage signaling kinase and as a novel ligand for intrinsic cell death proteins to delay damage-induced apoptosis, and on ATR's regulation of XPA and the NER process for repair of UV-induced DNA adducts. ATR's regulatory role in the cytosolic-to-nuclear translocation of XPA will be discussed. In addition, recent findings elucidating a non-NER role for XPA in DNA metabolism and genome stabilization at ds-ssDNA junctions, as exemplified in prematurely aging progeroid cells, also will be reviewed.

Xia J, Sun R
Association between the polymorphisms in XPG gene and gastric cancer susceptibility in Chinese populations: A PRISMA-compliant meta-analysis.
Medicine (Baltimore). 2017; 96(42):e8213 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Several previous studies were carried out on the association between xeroderma pigmentosum group G (XPG) gene polymorphisms (including rs873601 G>A, rs2094258 C>T, rs2296147 T>C, and rs751402 C>T) and the risk of gastric cancer in Chinese populations. However, their conclusions were not consistent. Therefore, this meta-analysis was performed by us to investigate the association between the 4 potentially functional single nucleotide polymorphisms (SNPs) of XPG gene and gastric cancer risk.
METHODS: The eligible literatures were identified through PubMed, Embase, Ovid MEDLINE, Web of Science, CNKI, and Wan fang databases up to July 2017. Finally, 5 studies for rs873601, 7 studies for rs2094258, 4 studies for rs2296147, and 8 studies for rs751402 were used for the current meta-analysis.
RESULTS: Of the 4 included SNPs, only rs751402 was showed to be associated with the risk of gastric cancer [C vs T, odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.04-1.29; CC + CT vs TT, OR = 1.23, 95% CI = 1.00-1.52; CC vs CT + TT, OR = 1.15, 95% CI = 1.05-1.27; CC vs TT, OR = 1.35, 95% CI = 1.06-1.72; CC vs CT, OR = 1.13, 95% CI = 1.02-1.25].
CONCLUSION: The current meta-analysis demonstrated that the XPG gene polymorphism rs751402 was associated with increased susceptibility to gastric cancer in Chinese populations. However, studies with a larger number of subjects among different ethnic groups are needed to further validate the results.

Zhang C, Liao Z, Yu G, et al.
Study on association between ERCC5 single nucleotide polymorphism and susceptibility to esophageal cancer.
J BUON. 2017 Jul-Aug; 22(4):979-984 [PubMed] Related Publications
PURPOSE: DNA repair genes play important roles in the genesis of esophageal cancer, and their functional single nucleotide polymorphism (SNP) loci may affect the susceptibility to esophageal cancer through changing the capability of DNA damage repair.
METHODS: A total of 557 patients with esophageal squamous cell carcinoma and 1503 age- and gender-matched healthy people were selected in this study. The hospital-based case-control method and the candidate gene and functional locus-based SNP selection strategy were used to screen three functional SNPs, loci on excision repair cross complement 5 (ERCC5): rs2296147, rs873601 and rs2094258. Genotyping was performed using Taqman method. A logistic regression model was used to analyze the relationship between the selected loci and the risk of esophageal cancer.
RESULTS: rs2296147 reduced the risk of esophageal cancer (CC vs TT: OR=0.79, 95% CI=0.64-0.97, p=0.027; additive model: OR=0.80, 95% CI=0.68-0.94, p=0.007). The results of stratified analysis showed that rs2296147 could reduce the susceptibility to esophageal cancer in women, non-smokers, drinkers and non-drinkers. No correlation between rs873601 and rs2094258 and susceptibility to esophageal cancer was found. However, the combined effect analysis showed that rs2296147, rs873601 and rs2094258 could increase the risk of esophageal cancer (ptrend=0.006).
CONCLUSION: The results of this case-control study showed that the polymorphic locus on ERCC5, rs2296147, could reduce the risk of esophageal cancer, which will help further understand the pathogenesis of esophageal cancer.

Song X, Wang S, Hong X, et al.
Single nucleotide polymorphisms of nucleotide excision repair pathway are significantly associated with outcomes of platinum-based chemotherapy in lung cancer.
Sci Rep. 2017; 7(1):11785 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Nucleotide excision repair (NER) pathway plays critical roles in repairing DNA disorders caused by platinum. To comprehensively understand the association between variants of NER and clinical outcomes of platinum-based chemotherapy, 173 SNPs in 27 genes were selected to evaluate association with toxicities and efficiency in 1004 patients with advanced non-small cell lung cancer. The results showed that consecutive significant signals were observed in XPA, RPA1, POLD1, POLD3. Further subgroup analysis showed that GTF2H4 presented consecutive significant signals in clinical benefit among adenocarcimoma. In squamous cell carcinoma, rs4150558, rs2290280, rs8067195 were significantly associated with anemia, rs3786136 was significantly related to thrombocytopenia, ERCC5 presented consecutive significant signals in response rate. In patients receiving TP regimen, significant association presented in neutropenia, thrombocytopenia and gastrointestinal toxicity. Association with anemia and neutropenia were found in GP regimen. rs4150558 showed significant association with anemia in NP regimen. In patients > 58, ERCC5 showed consecutive significant signals in gastrointestinal toxicity. Survival analysis showed SNPs in POLD2, XPA, ERCC6 and POLE were significantly associated with progression free survival, SNPs in GTF2H4, ERCC6, GTF2HA, MAT1, POLD1 were significantly associated with overall survival. This study suggests SNPs in NER pathway could be potential predictors for clinical outcomes of platinum-based chemotherapy among NSCLC.

Su Y, Yang C, Zhang Z
The Association Between XPG Gene Polymorphism and Gastric Cancer Risk.
Genet Test Mol Biomarkers. 2017; 21(10):619-624 [PubMed] Related Publications
PURPOSE: Studies exploring the association between the Xeroderma pigmentosum group G (XPG) gene polymorphisms and gastric cancer (GC) risk provide conflicting findings. Thus, this meta-analysis was performed.
MATERIALS AND METHODS: The PubMed and EMBASE databases were comprehensively searched to identify studies for the inclusion in the meta-analysis. The strength of the association was evaluated by calculating pooled odds ratios and 95% confidence intervals.
RESULTS: Nine case-control studies involving 3540 cases and 3953 controls were included in the meta-analysis, which revealed that the XPG rs751402 polymorphism is positively associated with GC risk and could be viewed as a risk factor of GC in three genetic models.
CONCLUSION: The XPG gene rs751402 polymorphism is associated with an increased risk of GC in Chinese Han populations. This finding should be verified by larger studies that include additional ethnic groups.

Han C, Huang X, Hua R, et al.
The association between XPG polymorphisms and cancer susceptibility: Evidence from observational studies.
Medicine (Baltimore). 2017; 96(32):e7467 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Exposure to environmental carcinogens can cause damages to DNA. If not properly repaired, the DNA damages may increase the risk of carcinogenesis. Xeroderma pigmentosum group G (XPG) gene is an essential gene in the nucleotide excision repair (NER) pathway. The association between XPG polymorphisms and cancer susceptibility has been the focus of attention in the molecular epidemiology of cancer. However, the conclusions have been divergent. Therefore, we conducted a comprehensive meta-analysis to precisely evaluate the association of 3 frequently investigated XPG polymorphisms (rs751402, rs873601, and rs2296147) with cancer risk.
METHODS: Pubmed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant studies in English and Chinese. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the association between XPG polymorphisms (rs751402, rs873601, and rs2296147) and cancer risk.
RESULTS: Twenty-three studies were included. Overall, there was no significant association between rs751402 polymorphism and overall cancer risk under the 5 gene models. However, we observed strong correlation between rs751402 polymorphism and gastric cancer (C vs T: OR=1.21, 95% CI = 1.00-1.26, P = .045; TC vs CC: OR = 1.12, 95% CI = 1.00-1.24, P = .041; TC/TT vs CC: OR = 1.13, 95% CI = 1.02-1.26, P = .020). There was a significant correlation between rs873601 polymorphism and cancer risk under the homozygous model (GG vs AA: OR = 1.16, 95% CI = 1.07-1.26, P = .001). Moreover, significant association with breast cancer was detected for rs873601 polymorphism under the allele contrast model (G vs A: OR = 1.10, 95% CI = 1.02-1.20, P = .021). In the subgroup of Asian, rs873601 polymorphism was related to the susceptibility to cancer (G vs A: OR = 1.07, 95% CI = 1.03-1.12, P = .010; GG vs AA: OR = 1.15, 95% CI = 1.06-1.26, P = .001; AG/AA vs GG: OR = 1.08, 95% CI = 1.01-1.15, P = .031; AA vs AG/GG: OR = 1.13, 95% CI = 1.05-1.21, P = .001). Significant association between rs2296147 polymorphism and cancer risk were observed in Asian population (CT vs TT: OR = 0.93, 95% CI = 0.87-0.99, P = .036).
CONCLUSIONS: Our meta-analysis suggested that the rs873601 polymorphism was significantly associated with overall cancer risk. The moderate effects of rs751402 and rs2296147 polymorphism on cancer susceptibility might be highly dependent on cancer type and ethnicity, respectively. Large studies are needed to validate our findings, especially in Caucasian and African population.

Tan LM, Qiu CF, Zhu T, et al.
Genetic Polymorphisms and Platinum-based Chemotherapy Treatment Outcomes in Patients with Non-Small Cell Lung Cancer: A Genetic Epidemiology Study Based Meta-analysis.
Sci Rep. 2017; 7(1):5593 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Data regarding genetic polymorphisms and platinum-based chemotherapy (PBC) treatment outcomes in patients with NSCLC are published at a growing pace, but the results are inconsistent. This meta-analysis integrated eligible candidate genes to better evaluate the pharmacogenetics of PBC in NSCLC patients. Relevant studies were retrieved from PubMed, Chinese National Knowledge Infrastructure and WANFANG databases. A total of 111 articles comprising 18,196 subjects were included for this study. The associations of genetic polymorphisms with treatment outcomes of PBC including overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) were determined by analyzing the relative risk (RR), hazard ration (HR), corresponding 95% confidence interval (CI). Eleven polymorphisms in 9 genes, including ERCC1 rs11615 (OS), rs3212986 (ORR), XPA rs1800975 (ORR), XPD rs1052555 (OS, PFS), rs13181 (OS, PFS), XPG rs2296147 (OS), XRCC1 rs1799782 (ORR), XRCC3 rs861539 (ORR), GSTP1 rs1695 (ORR), MTHFR rs1801133 (ORR) and MDR1 rs1045642 (ORR), were found significantly associated with PBC treatment outcomes. These variants were mainly involved in DNA repair (EXCC1, XPA, XPD, XPG, XRCC1 and XRCC3), drug influx and efflux (MDR1), metabolism and detoxification (GSTP1) and DNA synthesis (MTHFR), and might be considered as potential prognostic biomarkers for assessing objective response and progression risk in NSCLC patients receiving platinum-based regimens.

Yu SN, Liu GF, Li XF, et al.
Evaluation of Prediction of Polymorphisms of DNA Repair Genes on the Efficacy of Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer: A Network Meta-Analysis.
J Cell Biochem. 2017; 118(12):4782-4791 [PubMed] Related Publications
This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820), and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation. This network meta-analysis combines direct and indirect evidence to assess the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC. We evaluated the predictive value through the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). A total of 26 eligible cohort studies were enrolled in this NMA. The pairwise meta-analysis indicated that in terms of overall response ratio (ORR), ERCC1 (rs11615), XRCC1 (rs25487, rs1799782), and XPD (rs13181) polymorphisms are associated with the efficacy of platinum-based chemotherapy in NSCLC. The result of this NMA suggests that there is no significant difference in predictive value of 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC patients. The rank of SUCRA values of the 14 SNPs in the eight DNA repair genes were: XPD (rs1799793)→ERCC1 (rs3212986)→XPA(rs1800975)→ERCC1(rs3212948)→XRCC1(rs25487)→XRCC3(rs861539)→APE1(rs3136820)→ERCC1(rs11615)→XRCC1(rs1799782)→RRM1(rs1042858)→XPD(rs13181)→XPG (rs1047768)→XPG(rs17655)→XRCC1(rs25489). ERCC1(rs11615), XRCC1(rs25487, rs1799782) and XPD(rs13181) polymorphisms were better predictors in evaluating the efficacy of platinum-based chemotherapy in NSCLC patients. J. Cell. Biochem. 118: 4782-4791, 2017. © 2017 Wiley Periodicals, Inc.

Qian T, Zhang B, Qian C, et al.
Association between common polymorphisms in ERCC gene and glioma risk: A meta-analysis of 15 studies.
Medicine (Baltimore). 2017; 96(20):e6832 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: A number of studies have investigated the roles of excision repair cross complementation group 1 (ERCC1), ERCC2, and ERCC5 genes polymorphisms in the development of glioma; however, the results were inconsistent. Here, we performed a meta-analysis to investigate the association between 6 polymorphisms in the ERCC genes (rs3212986, rs11615, rs13181, rs1799793, rs238406, rs17655) and glioma risk.
METHODS: The PubMed, Embase, and Web of science were searched up to September 6, 2016, for studies on the association between ERCC polymorphisms and glioma risk. A fixed-effects or random-effects model was used to calculate the pooled odds ratios based on the results from the heterogeneity tests. Sensitivity and cumulative meta-analyses were also performed.
RESULTS: A total of 15 studies were eligible for the pooled analysis, conducted in 2 populations of ethnic descent: 8 Europeans and 7 Asians. The results showed that ERCC1 rs3212986 polymorphism was positively associated with glioma [AA vs CC: odds ratio (OR) = 1.298, 95% confidence interval (95% CI) = 1.043-1.230, P = .025]. Association of the ERCC2 rs13181 and rs1799793 polymorphisms was only observed in Asians (CC vs AA for rs13181: OR = 1.539, 95% CI = 1.122-2.109, P = .007; AA vs GG for rs1799793: OR = 1.474, 95% CI = 1.090-1.994, P = .012). However, no association was observed between glioma risk and ERCC1 rs11615, ERCC2 rs238406, and ERCC5 rs17655 polymorphisms. Moreover, sensitivity and cumulative meta-analyses confirmed the stability of the results.
CONCLUSIONS: Our meta-analysis indicated that the ERCC1 rs3212986 polymorphism and 2 polymorphisms in ERCC2 gene (rs13181 and rs1799793) contributed to the susceptibility of glioma.

Lonjou C, Damiola F, Moissonnier M, et al.
Investigation of DNA repair-related SNPs underlying susceptibility to papillary thyroid carcinoma reveals MGMT as a novel candidate gene in Belarusian children exposed to radiation.
BMC Cancer. 2017; 17(1):328 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Genetic factors may influence an individual's sensitivity to ionising radiation and therefore modify his/her risk of developing papillary thyroid carcinoma (PTC). Previously, we reported that common single nucleotide polymorphisms (SNPs) within the DNA damage recognition gene ATM contribute to PTC risk in Belarusian children exposed to fallout from the Chernobyl power plant accident. Here we explored in the same population the contribution of a panel of DNA repair-related SNPs in genes acting downstream of ATM.
METHODS: The association of 141 SNPs located in 43 DNA repair genes was examined in 75 PTC cases and 254 controls from the Gomel region in Belarus. All subjects were younger than 15 years at the time of the Chernobyl accident. Conditional logistic regressions accounting for radiation dose were performed with PLINK using the additive allelic inheritance model, and a linkage disequilibrium (LD)-based Bonferroni correction was used for correction for multiple testing.
RESULTS: The intronic SNP rs2296675 in MGMT was associated with an increased PTC risk [per minor allele odds ratio (OR) 2.54 95% CI 1.50, 4.30, P
CONCLUSIONS: These findings indicate that several genes acting in distinct DNA repair mechanisms contribute to PTC risk. Further investigation is needed to decipher the functional properties of the methyltransferase encoded by MGMT and to understand how alteration of such functions may lead to the development of the most common type of thyroid cancer.

Yeo J, Crawford EL, Zhang X, et al.
A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells.
BMC Cancer. 2017; 17(1):301 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Annual low dose CT (LDCT) screening of individuals at high demographic risk reduces lung cancer mortality by more than 20%. However, subjects selected for screening based on demographic criteria typically have less than a 10% lifetime risk for lung cancer. Thus, there is need for a biomarker that better stratifies subjects for LDCT screening. Toward this goal, we previously reported a lung cancer risk test (LCRT) biomarker comprising 14 genome-maintenance (GM) pathway genes measured in normal bronchial epithelial cells (NBEC) that accurately classified cancer (CA) from non-cancer (NC) subjects. The primary goal of the studies reported here was to optimize the LCRT biomarker for high specificity and ease of clinical implementation.
METHODS: Targeted competitive multiplex PCR amplicon libraries were prepared for next generation sequencing (NGS) analysis of transcript abundance at 68 sites among 33 GM target genes in NBEC specimens collected from a retrospective cohort of 120 subjects, including 61 CA cases and 59 NC controls. Genes were selected for analysis based on contribution to the previously reported LCRT biomarker and/or prior evidence for association with lung cancer risk. Linear discriminant analysis was used to identify the most accurate classifier suitable to stratify subjects for screening.
RESULTS: After cross-validation, a model comprising expression values from 12 genes (CDKN1A, E2F1, ERCC1, ERCC4, ERCC5, GPX1, GSTP1, KEAP1, RB1, TP53, TP63, and XRCC1) and demographic factors age, gender, and pack-years smoking, had Receiver Operator Characteristic area under the curve (ROC AUC) of 0.975 (95% CI: 0.96-0.99). The overall classification accuracy was 93% (95% CI 88%-98%) with sensitivity 93.1%, specificity 92.9%, positive predictive value 93.1% and negative predictive value 93%. The ROC AUC for this classifier was significantly better (p < 0.0001) than the best model comprising demographic features alone.
CONCLUSIONS: The LCRT biomarker reported here displayed high accuracy and ease of implementation on a high throughput, quality-controlled targeted NGS platform. As such, it is optimized for clinical validation in specimens from the ongoing LCRT blinded prospective cohort study. Following validation, the biomarker is expected to have clinical utility by better stratifying subjects for annual lung cancer screening compared to current demographic criteria alone.

Huang J, Liu X, Tang LL, et al.
XPG gene polymorphisms and cancer susceptibility: evidence from 47 studies.
Oncotarget. 2017; 8(23):37263-37277 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Xeroderma pigmentosum group G (XPG) is a single-strand-specific DNA endonuclease that functions in the nucleotide excision repair pathway. Genetic variations in XPG gene can alter the DNA repair capacity of this enzyme. We evaluated the associations between six single nucleotide polymorphisms (SNPs) in XPG (rs1047768 T>C, rs2296147 T>C, rs2227869 G>C, rs2094258 C>T, rs751402 C>T, and rs873601 G>A) and cancer risk. Forty-seven studies were identified in searches of the PubMed, Scopus, Web of Science, China National Knowledge Infrastructure, and WanFang databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed or random effects model. We found that rs873601 G>A was associated with an increased overall cancer risk (AA vs. GG: OR = 1.14, 95% CI = 1.06-1.24; GA/AA vs. GG: OR = 1.08, 95% CI = 1.02-1.15; A vs. G: OR = 1.06, 95% CI = 1.02-1.10). In a stratified analysis, rs1047768 T>C was associated with an increased risk of lung cancer, rs2227869 G>C was associated with a decreased risk of cancer in population-based studies, and rs751402 C>T and rs873601 G>A were associated with the risk of gastric cancer. Our data indicate that rs873601 G>A is associated with cancer susceptibility.

Borchiellini D, Etienne-Grimaldi MC, Bensadoun RJ, et al.
Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer.
Oral Oncol. 2017; 67:70-76 [PubMed] Related Publications
INTRODUCTION: Single nucleotide polymorphisms (SNPs) of DNA repair and apoptosis genes have been associated with outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy (RT). Our goal was to conduct a candidate gene study in HNSCC patients receiving RT or chemoRT.
METHODS: 122 non-resectable HNSCC patients undergoing RT (N=38) or chemoRT (N=84) between 1992 and 2006 were retrospectively analyzed. ERCC1 Lys259Thr (rs735482), ERCC2 Lys751Gln (rs13181), ERCC5 His46His C>T (rs1047768), XRCC1 Arg399Gln (rs25487), TP53 Arg72Pro (rs1042522) and MDM2 309T>G (rs2279744) were analyzed on tumor DNA. SNP profile was considered to assess RT-related toxicity.
RESULTS: All 120 evaluable patients experienced RT-related toxicity at any time. Among them, 83% had G3-4 acute side-effects during RT, mainly dysphagia, mucositis, epithelitis and/or xerostomia (DMEX). 28/105 patients (27%) had early G3-4 toxicity up to 3months after the end of RT. 29/96 patients (30%) had G3-4 late toxicity thereafter. The presence of G allele of MDM2 or Thr allele of ERCC1 was associated with a significantly higher risk of acute and/or early DMEX toxicity. The MDM2 309GG genotype was linked to a higher risk of acute G3-4 dermatitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Pro allele of TP53 72 was associated with a higher risk of G3-4 osteoradionecrosis.
CONCLUSION: Relevant SNPs in DNA repair (ERCC1 and ERCC5) and apoptosis (MDM2 and TP53) genes might influence the severity of radiation-related side-effects in HNSCC patients. Prospective clinical SNP-based validation studies are needed on these bases.

Pérez-Ramírez C, Cañadas-Garre M, Molina MÁ, et al.
Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer.
Mutat Res. 2017 Jan - Mar; 771:32-58 [PubMed] Related Publications
Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-β pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-β, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.

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