Gene Summary

Gene:XPC; XPC complex subunit, DNA damage recognition and repair factor
Aliases: XP3, RAD4, XPCC, p125
Summary:The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA repair protein complementing XP-C cells
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 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: XPC (cancer-related)

Teng X, Fan XF, Li Q, et al.
XPC inhibition rescues cisplatin resistance via the Akt/mTOR signaling pathway in A549/DDP lung adenocarcinoma cells.
Oncol Rep. 2019; 41(3):1875-1882 [PubMed] Related Publications
Xeroderma pigmentosum, complementation group C (XPC) is an accessory recognition gene involved in the nucleotide excision repair (NER) pathway, which is activated during the initial DNA damage recognition stage. It participates in the regulation of DNA damage‑induced proliferation and apoptosis. Emerging evidence demonstrates that upregulation of XPC increases the resistance of several tumor cell types to cytotoxic drugs. In addition, it can predict poor patient outcome for non‑small cell lung cancer (NSCLC). However, the mechanisms linking upregulation of XPC and drug resistance in lung cancer are still unclear. In the present study, we aimed to confirm whether XPC was involved in the reversal of the cisplatin (DDP) resistance in drug‑resistant A549/DDP lung adenocarcinoma cells. RT‑PCR and western blot assays were used to examine XPC mRNA and protein expression levels. Cell viability was assessed by CCK‑8 assay. The knockdown of XPC was achieved in A549/DDP cells using si‑RNA, whereas cell proliferation and apoptosis were assessed by wound healing assay and flow cytometric analysis, respectively. The median inhibitory concentration (IC50) value of DDP was assessed by CCK‑8 assay. Western blot assays were conducted for the examination of caspase‑9/3, Bax and Bcl‑2 protein levels, whereas the activation of the PI3K/Akt/mTOR signaling pathway was investigated in XPC‑knockdown cells. High expression of XPC was noted in A549/DDP cells compared with that in A549 cells, which was associated with DDP resistance. XPC silencing significantly inhibited A549/DDP cell proliferation and increased the induction of apoptosis. In addition, XPC knockdown decreased the expression levels of the Akt/mTOR signaling proteins and the expression of their downstream mediator. The data of the present study revealed that XPC inhibition rescued DDP resistance in lung adenocarcinoma cells, which was dependent on the Akt/mTOR signaling pathway. Collectively, XPC may be considered a new strategy for curing DDP‑resistant lung cancer and may improve the efficacy of conventional chemotherapy.

Said R, Bougatef K, Setti Boubaker N, et al.
Polymorphisms in XPC gene and risk for prostate cancer.
Mol Biol Rep. 2019; 46(1):1117-1125 [PubMed] Related Publications
Single nucleotide polymorphisms (SNP) in repair gene DNA such as XPC gene can reduce the DNA repair capacity (DRC). Reduced DRC induce genetic instability and may increase the susceptibility to prostate cancer (PC). We conducted a case-controls study to examine the relationship between XPC Lys939Gln and XPC-PAT polymorphisms and the risk for prostate cancer in Tunisian population. We have also correlated molecular results with clinical parameters (Gleason score and TNM status) and lifestyle factors (tobacco status, alcohol consumption, and exposition to professional risk factors) of prostate cancer patients. We have found that the XPC Lys939Gln polymorphism was not associated with a risk of prostate cancer. However the XPC PAT I/I genotype was found to be associated with 3.83-fold increased risk of prostate cancer compared to controls (p = 0.00006; OR 3.83; 95% CI (1.83-8.05)). The test of linkage disequilibrium showed that XPC-PAT polymorphism is in linkage disequilibrium with XPC Lys939Gln variants. The combined analysis of XPC Lys939Gln and XPC-PAT variants showed that patients who inherited (Lys/Gln + PAT D/D) genotypes were protected against prostate cancer development compared to controls. In the other hand, no significant association has been found between XPC polymorphisms and clinical parameters or between XPC polymorphisms and lifestyle factors.

Martin-Morales L, Rofes P, Diaz-Rubio E, et al.
Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.
PLoS One. 2018; 13(9):e0203885 [PubMed] Free Access to Full Article Related Publications
Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.

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

Bidon B, Iltis I, Semer M, et al.
XPC is an RNA polymerase II cofactor recruiting ATAC to promoters by interacting with E2F1.
Nat Commun. 2018; 9(1):2610 [PubMed] Free Access to Full Article Related Publications
The DNA damage sensor XPC is involved in nucleotide excision repair. Here we show that in the absence of damage, XPC co-localizes with RNA polymerase II (Pol II) and active post-translational histone modifications marks on a subset of class II promoters in human fibroblasts. XPC depletion triggers specific gene down-expression due to a drop in the deposition of histone H3K9 acetylation mark and pre-initiation complex formation. XPC interacts with the histone acetyltransferase KAT2A and specifically triggers the recruitment of the KAT2A-containing ATAC complex to the promoters of down-expressed genes. We show that a strong E2F1 signature characterizes the XPC/KAT2A-bound promoters and that XPC interacts with E2F1 and promotes its binding to its DNA element. Our data reveal that the DNA repair factor XPC is also an RNA polymerase II cofactor recruiting the ATAC coactivator complex to promoters by interacting with the DNA binding transcription factor E2F1.

Yadav SK, Singh S, Gupta S, et al.
Modulation of risk of squamous cell carcinoma head and neck in North Indian population with polymorphisms in xeroderma pigmentosum complementation Group C gene.
J Cancer Res Ther. 2018 Apr-Jun; 14(3):651-657 [PubMed] Related Publications
Background: Genetic variations in nucleotide excision repair genes can alter the risk of squamous cell carcinoma of head and neck (SCCHN).
Materials and Methods: The present study has genotyped 334 subjects from North Indian population for xeroderma pigmentosum complementation Group C (XPC) rs2228001A>C, XPC rs77907221 polyadenylate (PAT) deletion/insertion (D/I), xeroderma pigmentosum complementation Group D - rs13181A>C, and xeroderma pigmentosum complementation Type G rs17655 G>C polymorphisms with polymerase chain reaction (PCR)-restriction-fragment length polymorphism or allele-specific PCR methods.
Results: Compared to D allele, I allele for XPC PAT D/I polymorphism was associated with significantly decreased the risk of SCCHN (odds ratios = 0.67, 95% confidence interval [CI] =0.48-0.94, P = 0.03). Haplotype CI constituted from XPC polymorphisms was also associated with decreased risk of SCCHN (P = 0.004). In contrast, haplotype Crohn's disease significantly increased the risk for SCCHN (P < 0.00). A significant early onset of SCCHN was observed in individuals with CC genotype for XPC A>C polymorphism (P = 0.004).
Conclusion: Our results suggest a possible risk modulation for SCCHN with XPC polymorphisms in North Indian population.

Xu Y, Qin Q, Chen R, et al.
SIRT1 promotes proliferation, migration, and invasion of breast cancer cell line MCF-7 by upregulating DNA polymerase delta1 (POLD1).
Biochem Biophys Res Commun. 2018; 502(3):351-357 [PubMed] Related Publications
Sirtuin 1 (SIRT1), class III histone deacetylase, plays an important character in cell proliferation, cell cycle, apoptosis, energy metabolism and DNA repair. In recent years, researchers have attached increasing attention on the role of SIRT1 in tumorigenesis, development and drug resistance. The effect of SIRT1 on breast cancer is still controversial and its exact role remains to be elucidated. In the present study, we investigated the significant role of SIRT1 in breast cancer by exploring the effect of SIRT1 on DNA polymerase delta1 (POLD1), the gene coding for DNA polymerase δ catalytic subunit p125. Immunohistochemistry showed that the protein expression level of SIRT1 was higher in breast cancer tissues relative to adjacent normal tissues. Knockdown of SIRT1 by shRNA decreased the proliferation, migration, and invasion of human breast cancer cell line MCF-7, while the overexpression of SIRT1 promoted the proliferation, migration, and invasion of MCF-7 cells. Clinically, the immunohistochemistry results revealed that the expression of SIRT1 was positively correlated with p125. Further analysis demonstrated that silencing of SIRT1 increased the expression of p53, while the expression level of POLD1/p125 decreased, and the result by overexpressing SIRT1 was opposite. Collectively, these data suggest that SIRT1 is an oncogenic factor in breast cancer cells and can be involved in the progression of breast cancer by inhibiting p53 and activating POLD1. Our finding provides new insights into the mechanisms of breast cancer.

Mucha B, Pytel D, Markiewicz L, et al.
Nucleotide Excision Repair Capacity and XPC and XPD Gene Polymorphism Modulate Colorectal Cancer Risk.
Clin Colorectal Cancer. 2018; 17(2):e435-e441 [PubMed] Related Publications
BACKGROUND: Colorectal cancer (CRC) is leading malignant tumors to occur mainly in industrialized countries, where it exhibits one of the highest mortality rates. Up to 80% of all CRCs characterize a chromosomal instability (CIN) phenotype. The main challenge faced by scientist is to reveal the mechanism of CIN development. An often proposed model is defects in DNA repair in terms of efficiency and genetic variations that modulate the response to stimuli from the environment. The objectives of this research were to determine whether nucleotide excision repair (NER) might affect CRC risk.
MATERIALS AND METHODS: The first part of the study concerns NER efficiency. In the second part we selected 2 common single nucleotide polymorphisms within genes involved in NER (Xeroderma pigmentosum group C (XPC) Lys939Gln, Xeroderma pigmentosum group D (XPD) Lys751Gln) to determine the relation between them and CRC risk. The restriction fragment length polymorphism-polymerase chain reaction method was used for genotyping of 221 CRC patients vs. 270 cancer-free individuals. The isotopic labeling in vitro assay was used to evaluate NER capacity in lymphocytes and tissue protein extracts.
RESULTS: We observed a significantly decreased level of NER capacity (P = .025) in lymphocytes delivered from CRC patients compared with healthy ones. Polymorphism screening points to higher CRC risk for the Gln939Gln genotype (P = .02) and Gln allele (P = .002) of the XPC gene.
CONCLUSION: Taken together, our findings suggest a potential role for NER in CRC.

Perloy A, Schouten LJ, van den Brandt PA, et al.
The Role of Genetic Variants in the Association between Dietary Acrylamide and Advanced Prostate Cancer in the Netherlands Cohort Study on Diet and Cancer.
Nutr Cancer. 2018 May-Jun; 70(4):620-631 [PubMed] Related Publications
To investigate the association between dietary acrylanide and advanced prostate cancer, we examined acrylamide-gene interactions for advanced prostate cancer risk by using data from the Netherlands Cohort Study. Participants (n = 58,279 men) completed a baseline food frequency questionnaire (FFQ), from which daily acrylamide intake was calculated. At baseline, 2,411 men were randomly selected from the full cohort for case-cohort analysis. Fifty eight selected single nucleotide polymorphisms (SNPs) and two gene deletions in genes in acrylamide metabolism, DNA repair, sex steroid systems, and oxidative stress were analyzed. After 20.3 years of follow-up, 1,608 male subcohort members and 948 advanced prostate cancer cases were available for Cox analysis. Three SNPs showed a main association with advanced prostate cancer risk after multiple testing correction: catalase (CAT) rs511895, prostaglandin-endoperoxide synthase 2 (PTGS2) rs5275, and xeroderma pigmentosum group C (XPC) rs2228001. With respect to acrylamide-gene interactions, only rs1800566 in NAD(P)H quinone dehydrogenase 1 (NQO1) and rs2301241 in thioredoxin (TXN) showed a nominally statistically significant multiplicative interaction with acrylamide intake for advanced prostate cancer risk. After multiple testing corrections, none were statistically significant. In conclusion, no clear evidence was found for interaction between acrylamide intake and selected genetic variants for advanced prostate cancer risk.

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] Free Access to Full Article 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 (

Batar B, Mutlu T, Bostanci M, et al.
DNA repair and apoptosis: Roles in radiotherapy-related acute reactions in breast cancer patients.
Cell Mol Biol (Noisy-le-grand). 2018; 64(4):64-70 [PubMed] Related Publications
Normal tissue reactions are therapy limiting factor for the effectiveness of the radiotherapy in cancer patients. DNA repair and apoptosis are estimated to be critical players of adverse effects in response to radiotherapy. Our aim was to define the association of DNA repair (ERCC1 and XPC) and apoptotic (BCL2, CASP3 and NFKB1) gene expression, DNA damage levels, apoptosis changes and DNA repair gene variations with the risk of acute side effects in breast cancer patients. The study included 100 women with newly diagnosed breast cancer; an experimental case group (n=50) with acute side effects and the control group (n=50) without side effects. Gene expression was analyzed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Micronucleus (MN) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) assays were performed to compare the DNA damage levels. Apoptosis was examined by TDT-mediated dUTP-biotin nick end-labeling (TUNEL) staining. ERCC1 rs3212986 and XPC rs3731055 polymorphisms were genotyped by real-time PCR technique. No significantly correlation of DNA repair and apoptosis gene expression and DNA damage levels with acute side effects in response to radiotherapy. Also, there was no association between apoptosis levels and acute effects. ERCC1 rs3212986 CC genotype showed a protective effect against radiotherapy-induced acute reactions (p<0.001; OR: 0.21; 95% CI= 0.08-0.52). Our results suggest that apoptosis and DNA damage levels are not associated with acute radiosensitivity. DNA repair may affect the risk of acute reactions. Further studies are needed to validate the current findings.

Ijaz A, Basit S, Gul A, et al.
XPC gene mutations in families with xeroderma pigmentosum from Pakistan; prevalent founder effect.
Congenit Anom (Kyoto). 2019; 59(1):18-21 [PubMed] Related Publications
Xeroderma pigmentosum (XP) is a rare autosomal recessive skin disorder characterized by hyperpigmentation, premature skin aging, ocular and cutaneous photosensitivity, and increased risk of skin carcinoma. We investigated seven consanguineous XP families with nine patients from Pakistan. All the Patients exhibited typical clinical symptoms of XP since first year of life. Whole genome SNP genotyping identified a 14 Mb autozygous region segregating with the disease phenotype on chromosome 3p25.1. DNA sequencing of XPC gene revealed a founder homozygous splice site mutation (c.2251-1G>C) in patients from six families (A-F) and a homozygous nonsense mutation (c.1399C>T; p.Gln467*) in patients of family G. This is the first report of XPC mutations, underlying XP phenotype, in Pakistani population.

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] Free Access to Full Article 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.

Budden T, van der Westhuizen A, Bowden NA
Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma.
BMC Cancer. 2018; 18(1):100 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma.
METHODS: To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction.
RESULTS: Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin.
CONCLUSIONS: Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma.

Zhu B, Chen S, Wang H, et al.
The protective role of DOT1L in UV-induced melanomagenesis.
Nat Commun. 2018; 9(1):259 [PubMed] Free Access to Full Article Related Publications
The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis.

Horiuchi Y, Lin J, Shinojima Y, et al.
Characterizing key nucleotide polymorphisms of hepatitis C virus-disease associations via mass-spectrometric genotyping.
Int J Oncol. 2018; 52(2):441-452 [PubMed] Related Publications
As more than 80% of hepatocellular carcinoma patients in Japan also suffer from hepatitis C virus infections some time in their medical history, identifying genetic aberrations associated to hepatitis C virulence in these individuals remains a high priority in the diagnosis and treatment of hepatocellular carcinoma. From the BioBank Japan Project, we acquired 480 subjects of hepatocellular carcinoma, chronic hepatitis and liver cirrhosis, and genotyped 131 clinically relevant host single nucleotide polymorphisms to survey the potential association between certain risk alleles and genes to a patient's predisposition to hepatitis C and liver cancer. Among those polymorphisms, we found 12 candidates with statistical significance to support association with hepatitis C virus susceptibility and genetic predisposition to hepatocellular carcinoma. SNPs in genes such as XPC, FANCA, KDR and BRCA2 also suggested likely connections between hepatitis C virus susceptibility and the contraction of liver diseases. Single nucleotide polymorphisms reported here provided suggestions for genes as biomarkers and elucidated insights briefing the linkage of hepatitis C virulence to the alteration of healthy liver genomic landscape as well as liver disease progression.

Espi P, Parajuli S, Benfodda M, et al.
Clinical and genetic characteristics of xeroderma pigmentosum in Nepal.
J Eur Acad Dermatol Venereol. 2018; 32(5):832-839 [PubMed] Related Publications
BACKGROUND: Little is known about xeroderma pigmentosum (XP) in Himalayan countries.
OBJECTIVE: To describe clinical characteristics of XP in Nepal and investigate its genetic bases.
METHODS: This study was carried out on all consecutive patients referred for XP to a Nepalese tertiary referral centre in 2014-2015. Clinical data were collected using a standardized questionnaire. DNA was extracted from salivary samples, and next-generation sequencing (NGS) was conducted using a panel covering all 8 known XP genes (classical XP (XP-A to XP-G) and XP variant) and a skin cancer modifier gene, the melanocortin 1 receptor gene (MC1R).
RESULTS: Seventeen patients (median age: 15 years; range: 1-32) were included. Twelve had skin cancers (including a total of 8 squamous cell carcinomas, 60 basal cell carcinomas, ocular carcinomas requiring an orbital exenteration in 3 patients, but no melanoma). Fifteen patients carried the same homozygous non-sense XPC mutation c.1243C>T, p.R415X. A homozygous non-sense XPA mutation (p.W235X) was found in the only patient with a history of early severe sunburn reaction and associated neurological symptoms. Associated genetic alterations included heterozygous missense variants in XPD/ERCC2 gene and the presence of MC1R variant R163Q in 5 and 9 patients, respectively.
CONCLUSION: Although not previously reported, XP seems frequent in Nepal. Patients often presented with a very severe phenotype after a long history of excessive sun exposure without knowledge of the disease. Fifteen of 17 had the same p.R415X XPC mutation, which seems very specific of XP in Nepal, suggesting a founder effect. NGS analyses frequently revealed associated genetic alterations which could play a modifier role in the clinical expression of the disease.

Ahmed T, Nawaz S, Noreen R, et al.
A 3' untranslated region polymorphism rs2304277 in the DNA repair pathway gene OGG1 is a novel risk modulator for urothelial bladder carcinoma.
Ann Hum Genet. 2018; 82(2):74-87 [PubMed] Related Publications
Altered DNA repair capacity may affect an individual's susceptibility to cancers due to compromised genomic integrity. This study was designed to elucidate the association of selected polymorphisms in DNA repair genes with urothelial bladder carcinoma (UBC). OGG1 rs1052133 and rs2304277, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs2228001, and XPD rs13181 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 200 UBC cases and 200 controls. We found association of OGG1 rs2304277 [odds ratio (OR)

Özgöz A, Hekimler Öztürk K, Yükseltürk A, et al.
Genetic Variations of DNA Repair Genes in Breast Cancer.
Pathol Oncol Res. 2019; 25(1):107-114 [PubMed] Related Publications
Genetic variations in DNA repair genes may affect DNA repair capacity therefore increase risk for cancer. In our study, we evaluted the relation between DNA repair gene polymorphisms XRCC1 rs1799782, rs25487, rs25489; XPC rs2228000, rs2228001; XPD rs1799793, rs13181; XRCC3 rs861539; RAD51B rs10483813, rs1314913 and breast cancer risk for 202 Turkish cases in total, in which 102 patients with breast cancer and 100 controls. Genotyping of the DNA samples was carried out by multiplex PCR and matrix-assisted laser desorption/ionization mass spectrometry with time of flight measurement (MALDI-TOF) using Sequenom MassARRAY 4 analyzer. Genotype and allele distributions were calculated between the groups. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. rs25487 AA genotype and A allele was found to be increased in the control group (respectively, OR 0.16 95% CI 0.02-1.06, p = 0.058; OR 1.55, 95% CI 1.01-2.36, p = 0.043) and rs861539 T allele was found to be decreased in the patient group (OR 1.53, 95% CI 1.01-2.30, p = 0.049). No association with breast cancer was found for the remaining SNPs. Our findings suggest that XRCC1 rs25487 AA genotype and A allele, XRCC3 rs861539 T allele may have protective effects in breast cancer for Turkish population.

Zhang R, Jia M, Xue H, et al.
Genetic variants in ERCC1 and XPC predict survival outcome of non-small cell lung cancer patients treated with platinum-based therapy.
Sci Rep. 2017; 7(1):10702 [PubMed] Free Access to Full Article Related Publications
Nucleotide excision repair (NER) plays a vital role in platinum-induced DNA damage during chemotherapy. We hypothesize that regulatory single nucleotide polymorphisms (rSNPs) of the core NER genes modulate clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy (PBS). We investigated associations of 25 rSNPs in eight NER genes with progression free survival (PFS) and overall survival (OS) in 710 NSCLC patients. We found that ERCC1 rs3212924 AG/GG and XPC rs2229090 GC/CC genotypes were associated with patients' PFS (HR

Cleaver JE
Transcription coupled repair deficiency protects against human mutagenesis and carcinogenesis: Personal Reflections on the 50th anniversary of the discovery of xeroderma pigmentosum.
DNA Repair (Amst). 2017; 58:21-28 [PubMed] Related Publications
Xeroderma pigmentosum (XP) patients who lack the main damage recognition protein for global genome repair (GGR), XPC, have greatly increased skin cancer rates and elevated mutation frequencies originating from unrepaired ultraviolet photoproducts in the nontranscribed regions of the genome and in nontranscribed strands of expressed genes. But they show no increased mutations in transcribed strands. In contrast, cancer is absent from Cockayne syndrome (CS) patients that have defective transcription coupled repair (TCR) despite severe photosensitivity, CS patients remarkably show no elevation of UV induced mutagenesis implying that defective TCR may be protective against mutagenesis and carcinogenesis. Mutation avoidance in CS is postulated to occur through arrested transcription that generates a tripled stranded R loop consisting of DNA double strands and a nascent mRNA strand. R loops result in S phase apoptosis or activation of ATM kinase that causes a delay in DNA replication until TCR, or transcript cleavage by TFIIS or RNAaseH, relieves the transcription block. Resumption of replication then occurs on repaired DNA without concomitant mutagenesis.

Zheng Y, Deng Z, Yin J, et al.
The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum-based chemotherapy.
Int J Cancer. 2017; 141(11):2336-2347 [PubMed] Related Publications
Genetic variations in genes involved in repairing platinum-induced DNA lesions may contribute to the toxicity of platinum-based chemotherapy. The role of single-nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross-links to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum-based chemotherapy. Statistically significant SNPs were then assessed for replication in an independent validation cohort of 781 NSCLC patients. We found that 7 SNPs were significant at p < 0.01 (RRM1 rs12806698, XPC rs2228000, XPF rs1799801, hMLH1 rs1800734, PMS2 rs1062372, REV3L rs462779 and FANCC rs4647554) in the discovery cohort. Among them, two SNPs (RRM1 rs12806698 and hMLH1 rs1800734) remained significant after Bonferroni correction. XPC rs2228000 showed a significant relationship with severe gastrointestinal toxicity in the validation cohort. When the two cohorts were combined, XPC rs2228000 presented better tolerance of severe hematologic toxicity, gastrointestinal toxicity and leukopenia (OR = 0.677, 95% CI: 0.510-0.899, p = 0.007; OR = 0.565, 95% CI: 0.368-0.869, p = 0.009; OR = 0.628, 95% CI: 0.439-0.899, p = 0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum-induced toxicities.

Sarin N, Engel F, Kalayda GV, et al.
Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest.
PLoS One. 2017; 12(7):e0181081 [PubMed] Free Access to Full Article Related Publications
The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

Ho V, Brunetti V, Peacock S, et al.
Exposure to meat-derived carcinogens and bulky DNA adduct levels in normal-appearing colon mucosa.
Mutat Res. 2017; 821:5-12 [PubMed] Related Publications
INTRODUCTION: Meat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa.
METHODS: Least squares regression was used to examine the relationship between meat-derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using
RESULTS: PhIP and higher meat mutagenicity exposures were not associated with levels of bulky DNA adducts in colon mucosa. The XPC polymorphism (rs2228001) was found to associate with bulky DNA adduct levels, whereby genotypes conferring lower DNA repair activity were associated with higher DNA adduct levels than the normal activity genotype. Among individuals with genotypes associated with lower DNA repair (XPD, rs13181 and rs1799179) or detoxification activity (GSTP1, rs1695), higher PhIP or meat mutagenicity exposures were associated with higher DNA adduct levels. Significant interactions between the XPC polymorphism (rs2228000) and both dietary PhIP and meat mutagenicity on DNA adduct levels was observed, but associations were inconsistent with the a priori hypothesized direction of effect.
CONCLUSION: Exposure to meat-derived carcinogens may be associated with increased DNA damage occurring directly in the colon among genetically susceptible individuals.

Betti M, Casalone E, Ferrante D, et al.
Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma.
Cancer Lett. 2017; 405:38-45 [PubMed] Related Publications
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos exposure than did all the other patients (p = 0.0015). This suggests that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis. This study shows that germline variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment.

Gu Y, Chang X, Dai S, et al.
Identification of four novel XPC mutations in two xeroderma pigmentosum complementation group C patients and functional study of XPC Q320X mutant.
Gene. 2017; 628:162-169 [PubMed] Related Publications
Xeroderma pigmentosum (XP) is a rare, recessive hereditary disease characterized by sunlight hypersensitivity and high incidence of skin cancer with clinical and genetic heterogeneity. We collected two unrelated Chinese patients showing typical symptoms of XPC without neurologic symptoms. Direct sequencing of XPC gene revealed that patient 1 carried IVS1+1G>A and c.958 C>T mutations, and patient 2 carried c.545_546delTA and c.2257_2258insC mutations. All these four mutations introduced premature terminal codons (PTCs) in XPC gene. The nonsense mutation c.958 C>T yielded truncated mutant Q320X, and we studied its function for global genome repair kinetics. Overexpressed Q320X mutant can localize to site of DNA damage, but it is defective in CPD and 6-4PP repair. Readthrough of PTCs is a new approach to treatment of genetic diseases. We found that aminoglycosides could significantly increase the full length protein expression of Q320X mutant, but NER defects were not rescued in vitro.

Doubaj Y, Smaili W, Laarabi FZ, Sefiani A
A novel frameshift mutation in the XPC gene in a Moroccan patient: a case report.
J Med Case Rep. 2017; 11(1):158 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Xeroderma pigmentosum is an autosomal recessive inherited disease. The diagnosis is essentially based on clinical findings and the family history. This genodermatosis is genetically heterogeneous; to date, nine genes have been associated to this disorder. Based on the result of many studies, xeroderma pigmentosum complementation group C is the most common form of xeroderma pigmentosum. A founder mutation in the XPC gene was reported in the Maghreb region of northern Africa. According to these findings, the Department of Medical Genetics in Rabat offers molecular diagnosis by screening for the recurrent mutation c.1643_1644delTG which represents 74% of all the probands with xeroderma pigmentosum.
CASE PRESENTATION: We describe the case of a 21-year-old Moroccan son of consanguineous parents diagnosed with xeroderma pigmentosum on the basis of sun-exposed skin abnormalities and bilateral ocular involvement. A molecular study led to the identification of a new frameshift insertion of four nucleotides in exon 9.
CONCLUSIONS: To the best of our knowledge, this mutation has not been described. The sequencing of the ninth exon should be proposed as first line molecular analysis for all Moroccan patients with xeroderma pigmentosum.

Lawania S, Singh N, Behera D, Sharma S
XPC Polymorphism and Risk for Lung Cancer in North Indian Patients Treated with Platinum Based Chemotherapy and Its Association with Clinical Outcomes.
Pathol Oncol Res. 2018; 24(2):353-366 [PubMed] Related Publications
Xeroderma pigmentosum complementation group C plays an important role in the human repair system. As reported in previous studies its polymorphism are associated with lung cancer susceptibility. The purpose of this study is to investigate the association of XPC gene with lung cancer susceptibility, overall response and clinical outcomes amongst North Indians. A hospital based study of 370 lung cancer cases and 370 healthy controls was conducted and genotypes were determined using PCR-RFLP assay. Results were assessed using logistic linear regression adjusted for age, sex and smoking status. Survival analysis was conducted using Kaplan-Meier survival analysis and Cox regression analysis. The treatment outcomes of 167 lung cancer patients treated with platinum based chemotherapy were evaluated.The mutant genotypic variant of XPC Lys

Mori MP, Costa RA, Soltys DT, et al.
Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress.
Sci Rep. 2017; 7(1):155 [PubMed] Free Access to Full Article Related Publications
Genomic instability drives tumorigenesis and DNA repair defects are associated with elevated cancer. Metabolic alterations are also observed during tumorigenesis, although a causal relationship between these has not been clearly established. Xeroderma pigmentosum (XP) is a DNA repair disease characterized by early cancer. Cells with reduced expression of the XPC protein display a metabolic shift from OXPHOS to glycolysis, which was linked to accumulation of nuclear DNA damage and oxidants generation via NOX-1. Using XP-C cells, we show that mitochondrial respiratory complex I (CI) is impaired in the absence of XPC, while complex II (CII) is upregulated in XP-C cells. The CI/CII metabolic shift was dependent on XPC, as XPC complementation reverted the phenotype. We demonstrate that mitochondria are the primary source of H

Oba A, Shimada S, Akiyama Y, et al.
ARID2 modulates DNA damage response in human hepatocellular carcinoma cells.
J Hepatol. 2017; 66(5):942-951 [PubMed] Related Publications
BACKGROUND & AIMS: Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities.
METHODS: We established the ARID2 knockout human HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions.
RESULTS: Bioinformatic analysis indicated that UV-response genes were negatively regulated in the ARID2 knockout cells, and they were sensitized to UV irradiation. ARID2 depletion attenuated nucleotide excision repair (NER) of DNA damage sites introduced by exposure to UV as well as chemical compounds known as carcinogens for HCC, benzo[a]pyrene and FeCl
CONCLUSIONS: We provide evidence that ARID2 knockout could contribute to disruption of NER process through inhibiting the recruitment of XPG, resulting in susceptibility to carcinogens and potential hypermutation. These findings have implications for therapeutic targets in cancers harboring ARID2 mutations.
LAY SUMMARY: Recent genomic studies have identified frequent mutations of ARID2, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, in hepatocellular carcinoma, but it is not still understood how ARID2 exhibits tumor suppressor activities. In current study, we provided evidence that ARID2 knockout could contribute to disruption of DNA repair process, resulting in susceptibility to carcinogens and potential hypermutation. These findings have far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations.

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