Gene Summary

Gene:ERCC4; ERCC excision repair 4, endonuclease catalytic subunit
Summary:The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA repair endonuclease XPF
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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 11 March, 2017 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: ERCC4 (cancer-related)

Ravegnini G, Nannini M, Simeon V, et al.
Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.
Tumour Biol. 2016; 37(10):13413-13423 [PubMed] Related Publications
DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST.

Liu K, Jiang Y
Polymorphisms in DNA Repair Gene and Susceptibility to Glioma: A Systematic Review and Meta-Analysis Based on 33 Studies with 15 SNPs in 9 Genes.
Cell Mol Neurobiol. 2017; 37(2):263-274 [PubMed] Related Publications
At present, many publications have evaluated the correlation between the DNA repair gene polymorphisms and glioma susceptibility. However, the results remain inconclusive. The aim of this research is to exhaustively assess the association of genetic polymorphisms in DNA repair genes with glioma risk in human. Meta-analysis method was conducted, and 33 studies with 15 SNPs in 9 genes were included (12553 glioma cases and 17178 controls). Correlation strength was evaluated by odds ratio with a 95 % confidence interval. Rs1799782 T allele and rs25487A allele might bring about higher risk of glioma in Asian population. Rs1805377 G allele was an increased risk genetic factor of glioma. Asian carried with rs3212986 A allele was more likely to have glioma. Rs1800067 G allele was a risk factor of developing glioma. Carriers with rs12917 CC genotype in MGMT gene had higher risk of glioma in Caucasian than other non-CC genotype carriers. Carriers with rs1136410 T allele in PARP1 gene could more likely to develop glioma in Caucasian. This meta-analysis suggests that glioma susceptibility is associated with rs1799782 and rs25487 of X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), rs1805377 of XRCC4, rs1800067 of excision repair cross-complementing rodent repair deficiency complementation group 4 (ERCC4) and rs3212986 of ERCC1 in Asian population, and rs12917 of O-6-methylguanine-DNA methyltransferase (MGMT) and rs1136410 of poly(ADP-ribose) polymerase 1 (PARP1) in Caucasian population.

Ying MF, Zhao R
Role of single nucleotide polymorphisms of DNA repair genes in susceptibility to pancreatic cancer in Chinese population.
Genet Mol Res. 2016; 15(1) [PubMed] Related Publications
We conducted a case-control study to investigate the role of ERCC1-ERCC5 gene polymorphisms in the risk of pancreatic cancer. This study included 195 patients who were newly diagnosed with histopathologically confirmed primary pancreatic cancer, and 254 controls were recruited from Sir Run Run Shaw Hospital, between January 2012 and December 2014. Genotyping of ERCC1 rs3212986 and rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, and ERCC5 rs2094258 polymorphisms was carried out using polymerase chain reaction coupled with restriction fragment length polymorphism. Unconditional logistic regression analyses showed that the TT genotype of ERCC1 rs3212986 was associated with an increased risk of pancreatic cancer, and the OR (95%CI) was 2.26 (1.21-4.22). However, we did not find a significant association between ERCC1 rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, and ERCC5 rs2094258 polymorphisms and risk of pancreatic cancer. In summary, we found that the presence of the ERCC1 rs3212986 polymorphism correlated with an increased risk of pancreatic cancer.

Bănescu C, Iancu M, Trifa AP, et al.
Influence of XPC, XPD, XPF, and XPG gene polymorphisms on the risk and the outcome of acute myeloid leukemia in a Romanian population.
Tumour Biol. 2016; 37(7):9357-66 [PubMed] Related Publications
XPC, XPD, XPF, and XPG genes are implicated in the nucleotide excision repair (NER) system. Gene polymorphisms in NER repair system may influence the individual's capacity to recognize and repair DNA lesions, thus increasing the cancer risk. We hypothesized that these gene polymorphisms might influence the probability of developing acute myeloid leukemia (AML). We investigated the XPC, XPD, XPF, and XPG gene polymorphisms in 108 AML cases and 163 healthy controls. Also cytogenetic analyses besides FLT3 and DNMT3A mutations status were investigated. We found that variant genotypes (heterozygous and homozygous) of XPD 2251A > C and 22541A > C and the heterozygous genotype of XPG 3507G > C were associated with the risk of developing AML (OR = 2.55; 95% CI = 1.53-4.25; p value <0.001; OR = 1.66, 95 % CI = 1.02-2.72; p value = 0.047, and OR = 2.36; 95 % CI = 1.32-4.21; p value = 0.004, respectively). No association was found between white blood cell counts, FLT3, DNMT3A mutations, cytogenetic risk group, and variant genotypes of none of the analyzed polymorphisms. Variant homozygous XPF 673C > T genotype was associated with higher dose of cytosine arabinoside treatment administrated to AML patients (p value = 0.04). No differences were found regarding survival time and variant genotype in the investigated gene polymorphisms with the exception of XPD 2251A > C. In conclusion, XPD 22541A > C, XPD 2251A > C, and XPG 3507G > C gene polymorphisms confer susceptibility to AML, while XPC 2920A > C, XPF-673C > T, XPF 11985A > G are not associated with AML.

Lin S, Lei K, Du W, et al.
Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism.
Int J Biochem Cell Biol. 2016; 71:24-34 [PubMed] Related Publications
The resistance to oxaliplatin (L-OHP) is a major obstacle to ideal therapeutic outcomes in colorectal cancer. Photodynamic therapy (PDT) induces tumor damage through photosensitizer-mediated oxidative cytotoxicity. Hypericin is a well-studied photosensitizer. In this study, we explored the role of hypericin-mediated PDT (HY-PDT) in sensitizing human colorectal cancer cells towards L-OHP. Pre-treatment with HY-PDT enhanced the anti-tumor activity of L-OHP via decreasing drug efflux and increasing platinum accumulation. Further research showed that HY-PDT-mediated resensitization of resistance cells towards L-OHP was dependent on regulation of MRP-2, instead of p-gp. HY-PDT was also found to inhibit intracellular glutathione (GSH) and Glutathione S-transferase (GST), suggesting the involvement of GSH-related detoxification in the sensitization effect. Additionally, enhanced DNA double-strand breaks (DSBs) was observed following HY-PDT/L-OHP combined treatment. HY-PDT lowered the removing rate of platinum from DNA and down-regulated the expression of ERCC1 and XPF, two critical enzymes involved in nucleotide excision repair (NER) pathway. GSH monoethyl ester (GSH-EE) antagonized HY-PDT-induced ROS and repressed sensitization to platinum. Taken together, HY-PDT mediated sensitization of L-OHP in human colorectal cancer is mediated by ROS, whose mechanism involves affecting drug efflux, GSH-related detoxification and NER-mediated DNA repair.

Sun Y, Tan L, Li H, et al.
Association of NER pathway gene polymorphisms with susceptibility to laryngeal cancer in a Chinese population.
Int J Clin Exp Pathol. 2015; 8(9):11615-21 [PubMed] Free Access to Full Article Related Publications
We systematically analyzed the association of nine SNPs of seven key NER pathway genes with the development of laryngeal cancer patients, and investigated whether NER pathway polymorphisms could serve as potential biomarkers for laryngeal cancer risk. 271 patients with pathologically proven laryngeal cancer and 271 control subjects were included in our study. Genotyping of ERCC1 rs11615 and rs2298881, ERCC2 rs13181 and rs50871, ERCC3 rs4150441, ERCC4 rs6498486, ERCC5 rs2094258, XPA rs2808668 and XPC rs2228001 were analyzed by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By conditional logistic regression analysis, individuals carrying the TT genotype of ERCC1 rs11615 were correlated with an increased risk of larynx cancer when compared with the CC genotype (OR=1.89, 95% CI=1.07-3.37; P value=0.02). Moreover, individuals with the GG genotype of ERCC2 rs50871 were associated with an elevated risk of larynx cancer when compare with the TT genotype (OR=2.03, 95% CI=1.15-3.63; P value=0.01). We found a significant interaction between ERCC2 rs50871 polymorphism and tobacco smoking in the risk of larynx cancer (P for interaction <0.05). In conclusion, our study showed that ERCC1 rs11615 and ERCC2 rs50871 polymorphisms could influence the risk of larynx cancer in Chinese population, particularly among smokers.

Zhao F, Shang Y, Zeng C, et al.
Association of single nucleotide polymorphisms of DNA repair genes in NER pathway and susceptibility to pancreatic cancer.
Int J Clin Exp Pathol. 2015; 8(9):11579-86 [PubMed] Free Access to Full Article Related Publications
In our study, we conducted a case-control study to investigate the association of ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XPC and DDB2 gene polymorphisms in the risk of pancreatic cancer. Between May 2012 and May 2014, a total of 246 patients with who were newly diagnosed with histopathologically confirmed primary pancreatic cancer and 246 controls were selected into our study. Genotyping of ERCC1 rs3212986 and rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, ERCC5 rs873601, XPA rs2808668, XPC rs2228000, XPC rs2228001 and DDB2 rs2029298 were analyzed using polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By conditional logistic regression analysis, individuals carrying with TT genotype of ERCC1 rs3212986 and GG genotype of ERCC2 rs13181 were associated with increased risk of pancreatic cancer when compared with wide-type genotype, and the adjusted ORs (95% CI) were 2.40 (1.29-4.52) and 2.27 (1.26-4.15), respectively. We found that individuals carrying with GT+TT genotype of ERCC1 rs3212986 and TG+GG genotype of ERCC2 rs1318 gene polymorphisms were correlated with higher risk of pancreatic cancer in smokers when compared with non-smokers, and the adjusted ORs (95% CI) were 1.89 (1.05-3.40) and 1.88 (1.06-3.34), respectively. In conclusion, our study suggests that ERCC1 rs3212986 and ERCC2 rs1318 gene polymorphisms contribute to the development of pancreatic cancer, especially in smokers.

Wang MJ, Zhu Y, Guo XJ, Tian ZZ
Genetic variability of genes involved in DNA repair influence treatment outcome in osteosarcoma.
Genet Mol Res. 2015; 14(3):11652-7 [PubMed] Related Publications
We conducted a perspective study to investigate the role of ERCC1 (rs11615), ERCC2 (rs13181 and rs1799793), ERCC4 (rs1800067), and ERCC5 (rs17655) in NER pathway in the prognosis of osteosarcoma patients. In total, 146 osteosarcoma patients were recruited between 2008 and 2013. ERCC1 rs11615, ERCC2 rs13181 and rs1799793, ERCC4 rs1800067, and ERCC5 rs17655 gene polymorphisms were assessed by polymerase chain reaction-restriction fragment length polymorphism assay. By multivariate Cox proportional hazards models, we found that carriers of ERCC1 rs11615 TT genotype showed significantly favorable survival compared to wide-type CC genotype, and the adjusted OR (95%CI) was 0.24 (0.08-0.96). Moreover, we found that subjects with ERCC2 rs1799793 AA genotype were associated with decreased hazards of death in multivariate analysis (HR = 0.22, 95%CI = 0.12-0.93). In conclusion, our results suggest that ERCC1 rs11615 and ERCC2 rs1799793 may be useful genetic prognostic markers for osteosarcoma in a Chinese population.

Brinkmeyer MK, David SS
Distinct functional consequences of MUTYH variants associated with colorectal cancer: Damaged DNA affinity, glycosylase activity and interaction with PCNA and Hus1.
DNA Repair (Amst). 2015; 34:39-51 [PubMed] Free Access to Full Article Related Publications
MUTYH is a base excision repair (BER) enzyme that prevents mutations in DNA associated with 8-oxoguanine (OG) by catalyzing the removal of adenine from inappropriately formed OG:A base-pairs. Germline mutations in the MUTYH gene are linked to colorectal polyposis and a high risk of colorectal cancer, a syndrome referred to as MUTYH-associated polyposis (MAP). There are over 300 different MUTYH mutations associated with MAP and a large fraction of these gene changes code for missense MUTYH variants. Herein, the adenine glycosylase activity, mismatch recognition properties, and interaction with relevant protein partners of human MUTYH and five MAP variants (R295C, P281L, Q324H, P502L, and R520Q) were examined. P281L MUTYH was found to be severely compromised both in DNA binding and base excision activity, consistent with the location of this variation in the iron-sulfur cluster (FCL) DNA binding motif of MUTYH. Both R295C and R520Q MUTYH were found to have low fractions of active enzyme, compromised affinity for damaged DNA, and reduced rates for adenine excision. In contrast, both Q324H and P502L MUTYH function relatively similarly to WT MUTYH in both binding and glycosylase assays. However, P502L and R520Q exhibited reduced affinity for PCNA (proliferation cell nuclear antigen), consistent with their location in the PCNA-binding motif of MUTYH. Whereas, only Q324H, and not R295C, was found to have reduced affinity for Hus1 of the Rad9-Hus1-Rad1 complex, despite both being localized to the same region implicated for interaction with Hus1. These results underscore the diversity of functional consequences due to MUTYH variants that may impact the progression of MAP.

Sun Y, Wu Y, Li W, et al.
Genetic polymorphisms in nucleotide excision repair pathway influences response to chemotherapy and overall survival in osteosarcoma.
Int J Clin Exp Pathol. 2015; 8(7):7905-12 [PubMed] Free Access to Full Article Related Publications
We analyzed the role of genetic polymorphisms of six important NER pathway genes in response to chemotherapy and clinical outcome of osteosarcoma patients. A prospective study including 172 osteosarcoma patients was conducted between January 2009 and January 2011. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for ERCC1 rs11615 and rs2298881, ERCC2 rs13181 and rs1799793, ERCC4 rs1800067, ERCC5 rs1047768, XPA 1800975, and XPC rs2228000 and rs2228001 gene polymorphisms. By logistic regression analysis, TT genotype of ERCC1 rs11615 genetic polymorphism was significant correlated with poor response to chemotherapy when compared with wide-type genotype (OR=0.27, 95% CI=0.10-0.71). AC and CC genotype of ERCC1 rs2298881 were significantly associated with poor response to chemotherapy when compared with AA genotype (For AC genotype, OR=0.45, 95% CI=0.21-0.97; for CC genotype, OR=0.19, 95% CI=0.06-0.58). By Cox proportional hazards regression analysis, TT genotype of ERCC1 rs11615 and CC genotype of ERCC1 rs2298881 suffered a 3.16 and 3.57-fold increased hazards of death (For ERCC1 rs11615, HR=3.16, 95% CI=1.19-9.16; for ERCC1 rs2298881, HR=3.57, 95% CI=1.10-11.35). In conclusion, our findings suggest that ERCC1 rs11615 and ERCC1 rs2298881 genetic polymorphisms are significantly associated with poor response to chemotherapy and unfavourable survival of osteosarcoma.

Kabziński J, Majsterek I, Dziki A, Mik M
The Role of the XPF Gene Polymorphism (Xrcc4) Ser835ser in the Risk of Malignant Transformation of Cells in the Colorectal Cancer.
Pol Przegl Chir. 2015; 87(2):83-5 [PubMed] Related Publications
UNLABELLED: Participation of DNA repair systems in the pathogenesis of cancer has been a suspected phenomenon for a long time. Decreased efficiency in DNA repair translates to their ability to fix and consequently leads to mutations and the process of carcinogenesis. Linking individual polymorphisms of DNA repair systems with an increased risk of colorectal cancer will allow the classification of patients to high-risk groups and their placement under preventive program. The aim of the study was to determine the effect of XPF gene polymorphism Ser835Ser on increasing the risk of colorectal cancer in the Polish population.
MATERIAL AND METHODS: as the material blood collected from 146 patients diagnosed with colon cancer was used. The control group consisted of 149 healthy subjects. Genotyping was performed by Taq- Man method.
RESULTS: The results indicate that genotype TCC/TCT is associated with an decreased risk of colorectal cancer (OR 0.574; CI 95% 0.335-0.984; p=0.043).
CONCLUSIONS: Based on these results, we conclude that the XPF gene polymorphism Ser835Ser may be associated with a decreased risk of colorectal cancer.

Manandhar M, Boulware KS, Wood RD
The ERCC1 and ERCC4 (XPF) genes and gene products.
Gene. 2015; 569(2):153-61 [PubMed] Free Access to Full Article Related Publications
The ERCC1 and ERCC4 genes encode the two subunits of the ERCC1-XPF nuclease. This enzyme plays an important role in repair of DNA damage and in maintaining genomic stability. ERCC1-XPF nuclease nicks DNA specifically at junctions between double-stranded and single-stranded DNA, when the single-strand is oriented 5' to 3' away from a junction. ERCC1-XPF is a core component of nucleotide excision repair and also plays a role in interstrand crosslink repair, some pathways of double-strand break repair by homologous recombination and end-joining, as a backup enzyme in base excision repair, and in telomere length regulation. In many of these activities, ERCC1-XPF complex cleaves the 3' tails of DNA intermediates in preparation for further processing. ERCC1-XPF interacts with other proteins including XPA, RPA, SLX4 and TRF2 to perform its functions. Disruption of these interactions or direct targeting of ERCC1-XPF to decrease its DNA repair function might be a useful strategy to increase the sensitivity of cancer cells to some DNA damaging agents. Complete deletion of either ERCC1 or ERCC4 is not compatible with viability in mice or humans. However, mutations in the ERCC1 or ERCC4 genes cause a remarkable array of rare inherited human disorders. These include specific forms of xeroderma pigmentosum, Cockayne syndrome, Fanconi anemia, XFE progeria and cerebro-oculo-facio-skeletal syndrome.

Shi ZH, Shi GY, Liu LG
Polymorphisms in ERCC1 and XPF gene and response to chemotherapy and overall survival of non-small cell lung cancer.
Int J Clin Exp Pathol. 2015; 8(3):3132-7 [PubMed] Free Access to Full Article Related Publications
We conducted a perspective study to assess the association between ERCC1 and XPF polymorphisms and response to chemotherapy and clinical outcome of NSCLC receiving chemotherapy. Between May 2009 and May 2011, a prospective study was conducted on 240 NSCLC cases. Genotypes of ERCC1 (rs11615, rs3212986 and rs2298881) and XPF (rs2276465 and rs6498486) were performed by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay. By conditional logistic regression analysis, patients carrying AA genotype of ERCC1 rs11615 showed more CR+PR to chemotherapy when compared with GG genotype, and the adjusted OR (95% CI) was 2.73 (1.21-6.18). By Cox regression analysis, AA genotype of ERCC1 rs11615 was associated with longer overall survival of NSCLC, and the adjusted HR (95% CI) was 0.38 (0.14-0.96). In conclusion, our study found that ERCC1 rs11615 polymorphism can influence the chemotherapy response and overall survival of NSCLC patients receiving cisplatin-based chemotherapy.

Tofuku Y, Nobeyama Y, Kamide R, et al.
Xeroderma pigmentosum complementation group F: Report of a case and review of Japanese patients.
J Dermatol. 2015; 42(9):897-9 [PubMed] Related Publications
Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by extraordinary sensitivity to sunlight, resulting in cutaneous malignant tumors. Among XP, XP-F presents relatively uniquely in Japanese. To clarify the characteristics of this group, we describe a case of XP-F and review Japanese cases previously reported. A 50-year-old Japanese woman was referred to us with multiple, variously sized, light- or dark-brown macules on the face and sunlight-exposed extremities. She had experienced bulla formation with approximately 10 min of sunlight exposure during her elementary school years. Her parents had been first cousins, and her mother and sister had photosensitivity. She showed no neurological or developmental abnormalities. Ultraviolet (UV) irradiation testing revealed normal levels for minimal erythema dose with UV-A and UV-B. Sensitivity to UV-C and DNA repair ability in the patient's fibroblasts were indicated between that in normal individuals and that in an XP-A patient. Complementation assay revealed that transfection of the XPF gene led most efficient DNA repair compared with the other XP genes. Therefore, the patient was diagnosed with XP-F. Twenty-three cases of Japanese patients (six males, 17 females) with XP-F have been reported, including the present case. Our review suggested a relatively high prevalence of 50% (11/22) for cutaneous malignant tumors. A significant difference was evident in the mean age at first medical consultation between patients with cutaneous malignant tumors (53.6 years) and patients without such tumors (30.8 years). This suggests that cutaneous malignant tumors could occur in the age range of 30-50 years in XP-F patients.

McNeil EM, Astell KR, Ritchie AM, et al.
Inhibition of the ERCC1-XPF structure-specific endonuclease to overcome cancer chemoresistance.
DNA Repair (Amst). 2015; 31:19-28 [PubMed] Related Publications
ERCC1-XPF is a structure-specific endonuclease that is required for the repair of DNA lesions, generated by the widely used platinum-containing cancer chemotherapeutics such as cisplatin, through the Nucleotide Excision Repair and Interstrand Crosslink Repair pathways. Based on mouse xenograft experiments, where ERCC1-deficient melanomas were cured by cisplatin therapy, we proposed that inhibition of ERCC1-XPF could enhance the effectiveness of platinum-based chemotherapy. Here we report the identification and properties of inhibitors against two key targets on ERCC1-XPF. By targeting the ERCC1-XPF interaction domain we proposed that inhibition would disrupt the ERCC1-XPF heterodimer resulting in destabilisation of both proteins. Using in silico screening, we identified an inhibitor that bound to ERCC1-XPF in a biophysical assay, reduced the level of ERCC1-XPF complexes in ovarian cancer cells, inhibited Nucleotide Excision Repair and sensitised melanoma cells to cisplatin. We also utilised high throughput and in silico screening to identify the first reported inhibitors of the other key target, the XPF endonuclease domain. We demonstrate that two of these compounds display specificity in vitro for ERCC1-XPF over two other endonucleases, bind to ERCC1-XPF, inhibit Nucleotide Excision Repair in two independent assays and specifically sensitise Nucleotide Excision Repair-proficient, but not Nucleotide Excision Repair-deficient human and mouse cells to cisplatin.

Gupta RK, Bajpai D, Singh N
Influence of Morinda citrifolia (Noni) on Expression of DNA Repair Genes in Cervical Cancer Cells.
Asian Pac J Cancer Prev. 2015; 16(8):3457-61 [PubMed] Related Publications
BACKGROUND: Previous studies have suggested that Morinda citrifolia (Noni) has potential to reduce cancer risk.
OBJECTIVE: The purpose of this study was to investigate the effect of Noni, cisplatin, and their combination on DNA repair genes in the SiHa cervical cancer cell line.
MATERIALS AND METHODS: SiHa cells were cultured and treated with 10% Noni, 10 μg/dl cisplatin or their combination for 24 hours. Post culturing, the cells were pelleted, RNA extracted, and processed for investigating DNA repair genes by real time PCR.
RESULTS: The expression of nucleotide excision repair genes ERCC1, ERCC2, and ERCC4 and base excision repair gene XRCC1 was increased 4 fold, 8.9 fold, 4 fold, and 5.5 fold, respectively, on treatment with Noni as compared to untreated controls (p<0.05). In contrast, expression was found to be decreased 22 fold, 13 fold, 16 fold, and 23 fold on treatment with cisplatin (p<0.05). However, the combination of Noni and cisplatin led to an increase of 2 fold, 1.6 fold, 3 fold, 1.2 fold, respectively (p<0.05).
CONCLUSIONS: Noni enhanced the expression of DNA repair genes by itself and in combination with cisplatin. However, high expression of DNA repair genes at mRNA level only signifies efficient DNA transcription of the above mentioned genes; further investigations are needed to evaluate the DNA repair protein expression.

Liu Y, Zhou R, Sulman EP, et al.
Genetic Modulation of Neurocognitive Function in Glioma Patients.
Clin Cancer Res. 2015; 21(14):3340-6 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Accumulating evidence supports the contention that genetic variation is associated with neurocognitive function in healthy individuals and increased risk for neurocognitive decline in a variety of patient populations, including cancer patients. However, this has rarely been studied in glioma patients.
EXPERIMENTAL DESIGN: To identify the effect of genetic variants on neurocognitive function, we examined the relationship between the genotype frequencies of 10,967 single-nucleotide polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase) and neurocognitive function in 233 newly diagnosed glioma patients before surgical resection. Four neuropsychologic tests that measured memory (Hopkins Verbal Learning Test-Revised), processing speed (Trail Making Test A), and executive function (Trail Making Test B, Controlled Oral Word Association) were examined.
RESULTS: Eighteen polymorphisms were associated with processing speed and 12 polymorphisms with executive function. For processing speed, the strongest signals were in IRS1 rs6725330 in the inflammation pathway (P = 2.5 × 10(-10)), ERCC4 rs1573638 in the DNA repair pathway (P = 3.4 × 10(-7)), and ABCC1 rs8187858 in metabolism pathway (P = 6.6 × 10(-7)). For executive function, the strongest associations were in NOS1 rs11611788 (P = 1.8 × 10(-8)) and IL16 rs1912124 (P = 6.0 × 10(-7)) in the inflammation pathway, and POLE rs5744761 (P = 6.0 × 10(-7)) in the DNA repair pathway. Joint effect analysis found significant gene polymorphism-dosage effects for processing speed (Ptrend = 9.4 × 10(-16)) and executive function (Ptrend = 6.6 × 10(-15)).
CONCLUSIONS: Polymorphisms in inflammation, DNA repair, and metabolism pathways are associated with neurocognitive function in glioma patients and may affect clinical outcomes.

Bajpai D, Banerjee A, Pathak S, et al.
Single nucleotide polymorphisms in the DNA repair genes in HPV-positive cervical cancer.
Eur J Cancer Prev. 2016; 25(3):224-31 [PubMed] Related Publications
Genetic variation in DNA repair genes can modulate DNA repair capacity and may be related to the risk of cancer. The human papillomavirus is considered to be a necessary but not sufficient cause for cervical cancer and, therefore, other factors contribute to the carcinogenesis. A hereditary component for this neoplasia has been reported. Evaluation of the association of six polymorphisms was carried out in the following DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), ERCC1 (Asp118Asp), ERCC2 (Lys751Gln), and ERCC4 (Arg415Gln). The cases (n=110) included 65 squamous cell carcinomas (SCCs) and 45 squamous intraepithelial lesions (SIL). Controls (n=68) were recruited from among women without cervical abnormalities. Genotypes were determined by PCR-restriction fragment length polymorphism and DNA sequencing. A positive association was observed between the polymorphisms of XRCC1 genes, that is, in codons 194 [P=0.001, odds ratio (OR)=20.1, 95% confidence interval (CI)=5.9-68.8], 280 (P=0.001, OR=5.4, 95% CI=2.3-12.6), and 399 (P=0.008, OR=4.2, 95% CI=1.5-12.1) and cervical cancer. SIL patients also showed a significant association with codon 194 (P=0.012, OR=3.8, 95% CI=1.3-10.6), but not with 280 (P=0.35) and 399 (P=0.81). A positive correlation was also found in ERCC4 Gln415Gln in both SCCs and SILs (P=0.001, OR=21.3, 95% CI=7.1-64.0 and P=0.001, OR=7.8, 95% CI=2.9-20.9, respectively). For ERCC2 Gln751Gln, the association was significant for both SCCs (P=0.001, OR=10.1, 95% CI=2.6-37.9) and SILs (P=0.001, OR=8.9, 95% CI=2.8-28.3). However, the risk of SCC did not appear to differ significantly among individuals with the ERCC1 Asp118Asp genotype (P=0.404). For SILs, it appeared to be a protective genotype (95% CI=0.1-0.7). This study indicates that variant types of DNA repair genes play an important role in modifying individual susceptibility to SCC.

Yang H, Li G, Li WF
Association between ERCC1 and XPF polymorphisms and risk of colorectal cancer.
Genet Mol Res. 2015; 14(1):700-5 [PubMed] Related Publications
We conducted a hospital-based case-control study to evaluate the association between polymorphisms in excision repair cross-complementing group 1-xeroderma pigmentosum group F (ERCC1-XPF) variants and the risk of colorectal cancer in a Chinese population. Genotyping of the ERCC1 rs2298881 and rs11615 and XPF rs2276466 polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. Colorectal cancer cases were more likely to be smokers, consume alcohol, have higher energy intake, and have a family history of cancer. Using conditional regression analysis, subjects carrying the ERCC1 rs2298881CC genotype and C allele showed a significantly increased risk of colorectal cancer compared with those carrying the AA genotype. However, we found no association between the rs11615 and rs2276466 polymorphisms and the risk of colorectal cancer. In conclusion, the ERCC1 rs2298881 polymorphism may be used as a predictive factor for determining the risk of colorectal cancer in a Chinese population. This finding may be useful for identifying the genetic characteristics of colorectal cancer and developing more efficient strategies for prevention and treatment.

Ceccaldi R, O'Connor KW, Mouw KW, et al.
A unique subset of epithelial ovarian cancers with platinum sensitivity and PARP inhibitor resistance.
Cancer Res. 2015; 75(4):628-34 [PubMed] Free Access to Full Article Related Publications
Platinum and PARP inhibitor (PARPi) sensitivity commonly coexist in epithelial ovarian cancer (EOC) due to the high prevalence of alterations in the homologous recombination (HR) DNA repair pathway that confer sensitivity to both drugs. In this report, we describe a unique subset of EOC with alterations in another DNA repair pathway, the nucleotide excision repair (NER) pathway, which may exhibit a discordance in sensitivities to these drugs. Specifically, 8% of high-grade serous EOC from The Cancer Genome Atlas dataset exhibited NER alterations, including nonsynonymous or splice site mutations and homozygous deletions of NER genes. Tumors with NER alterations were associated with improved overall survival (OS) and progression-free survival (PFS), compared with patients without NER alterations or BRCA1/2 mutations. Furthermore, patients with tumors with NER alterations had similar OS and PFS as BRCA1/2-mutated patients, suggesting that NER pathway inactivation in EOC conferred enhanced platinum sensitivity, similar to BRCA1/2-mutated tumors. Moreover, two NER mutations (ERCC6-Q524* and ERCC4-A583T), identified in the two most platinum-sensitive tumors, were functionally associated with platinum sensitivity in vitro. Importantly, neither NER alteration affected HR or conferred sensitivity to PARPi or other double-strand break-inducing agents. Overall, our findings reveal a new mechanism of platinum sensitivity in EOC that, unlike defective HR, may lead to a discordance in sensitivity to platinum and PARPi, with potential implications for previously reported and ongoing PARPi trials in this disease.

Qiu J, Wang X, Meng X, et al.
Attenuated NER expressions of XPF and XPC associated with smoking are involved in the recurrence of bladder cancer.
PLoS One. 2014; 9(12):e115224 [PubMed] Free Access to Full Article Related Publications
The varied NER genes and smoking are two important risk factors of bladder cancer, but the mechanism of the NER protein and smoking in cancer progression, however, remains unclear. In this report, we compared the expressions of NER genes in 79 bladder cancer tissues with or without any recurrence by real-time PCR and then analyzed the varied NER genes by immunochemistry in 219 bladder cancer tissue samples. Based on the clinical data, we analyzed the clinical value of varied NER genes and smoking in 219 bladder cancers by the Kaplan-Meier method and Cox proportional hazards regression. We found the expressions of the NER gene XPF and XPC were significantly lower in bladder cancer tissues with a recurrence compared with those without a recurrence at mRNA level. Also, the patients with the XPF and XPC defect had a statistically significant lower median recurrence-free survival time than those without the XPF and XPC defect, and smoking can make this difference more remarkable. Our results suggest that XPF and XPC expression may be a potential predictive factor for bladder cancer, and smoking can not only influence the recurrence of bladder cancer as a single factor but also aggravate the results of the XPF defect and XPC defect.

Yun H, Shi R, Yang Q, et al.
Over expression of hRad9 protein correlates with reduced chemosensitivity in breast cancer with administration of neoadjuvant chemotherapy.
Sci Rep. 2014; 4:7548 [PubMed] Related Publications
Human Rad 9 (hRad9), part of the Rad9-Hus1-Rad1 complex plays an important role in DNA damage repair as an up-stream regulator of checkpoint signaling, however little is known about its role in response to chemotherapy of breast cancer and whether hRad9 inhibition can potentiate the cytotoxic effects of chemotherapy on breast cancer cells remains to be elucidated. Fifty cases of breast cancer receiving neoadjuvant therapy were collected. All these cases were revised and classified into chemotherapy sensitive (CS) or chemotherapy resistant (CR) group according to the Miller and Payne (MP) grading system. Immunohistochemically, hRad9 positive tumours showed nuclear and/or cytoplasmic staining. hRad9 over-expression was associated with an impaired neoadjuvant chemotherapy response. A significant correlation was found between expression of hRad9 and Cyclin D1. In vitro, hRad9 was knocked down using siRNA in breast cancer cell line MCF-7 and MDA-MB-231. Deregulated expression of Rad9 accompanied by down expression of chk1 enhanced the sensitivity of human breast cancer cells to doxorubicin. Our work suggests that hRad9 might be a potential predictor for the response to chemotherapy in patients with breast cancer and its clinical value as a target for improving chemosensitivity needs further exploration.

Alter BP
Fanconi anemia and the development of leukemia.
Best Pract Res Clin Haematol. 2014 Sep-Dec; 27(3-4):214-21 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 genes, whose protein products collaborate in a DNA repair pathway. The major complications are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. A severe subset, due to mutations in FANCD1/BRCA2, has a cumulative incidence of cancer of 97% by age 7 years; the cancers are AML, brain tumors, and Wilms tumor; several patients have multiple events. Patients with the other genotypes (FANCA through FANCQ) have cumulative risks of more than 50% of marrow failure, 20% of AML, and 30% of solid tumors (usually head and neck or gynecologic squamous cell carcinoma), by age 40, and they too are at risk of multiple adverse events. Hematopoietic stem cell transplant may cure AML and MDS, and preemptive transplant may be appropriate, but its use is a complicated decision.

Lamba JK, Fridley BL, Ghosh TM, et al.
Genetic variation in platinating agent and taxane pathway genes as predictors of outcome and toxicity in advanced non-small-cell lung cancer.
Pharmacogenomics. 2014; 15(12):1565-74 [PubMed] Free Access to Full Article Related Publications
AIM: Lung carcinoma is the most common malignancy and the leading cause of cancer deaths worldwide. Although clinical factors including age, performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy, the genetic profile of individual patients may be an independent predictor of response and toxicity. The present study aimed to identify pharmacogenetic markers associated with clinical response and toxicity in patients with advanced non-small cell lung cancer (NSCLC) treated primarily with carboplatin and paclitaxel.
MATERIALS & METHODS: Genomic DNA samples from 90 adult male patients diagnosed with stage IIIB/IV NSCLC were genotyped for SNPs in candidate genes of relevance to platinating agents and paclitaxel and analyzed for association with survival and toxicities in univariate and multivariate models.
RESULTS: After adjusting for performance status and stage, SNPs in the drug transporters ABCB1 and ABCC1, as well as within NQO1 were associated with progression-free survival. With respect to hematological and nonhematological toxicities, SNPs in drug transporters (ABCB1 and ABCG2) were associated with thrombocytopenia, nausea and neutropenia, whereas SNPs in the DNA repair pathway genes ERCC4 and XPC were significantly associated with neutropenia and sensory neuropathy, respectively.
CONCLUSION: Our study evaluated and identified SNPs in key candidate genes in platinating agent and taxane pathways associated with outcome and toxicity in advanced NSCLC. If validated in large prospective studies, these findings might provide opportunities to personalize therapeutic strategies.

Chen ZH, Wang L, Luo LP
Association of DNA repair gene polymorphisms with response to chemotherapy and prognosis of gastric cancer.
Genet Mol Res. 2014; 13(3):7484-91 [PubMed] Related Publications
We investigated the correlation between the response to chemotherapy in patients and excision repair cross-complimenta-ry group 1 gene (ERCC1) and xeroderma pigmentosum complemen-tation group F gene (XPF) polymorphisms and the effect of these polymorphisms on the clinical outcome of gastric cancer. Samples from a total of 255 patients with newly diagnosed and histopatho-logically confirmed primary gastric cancer were collected in our study. The ERCC1 rs11615, ERCC1 rs2298881, XPF rs2276465, and XPF rs6498486 polymorphisms were genotyped. Among the 255 patients, the median follow-up time was 29.7 months. A total of 103 patients (40.4%) died from gastric cancer during the follow-up period. We observed that the XPF rs6498486 CC genotype and the XPF rs2276465 GG genotype were associated with response to che-motherapy, with odds ratios and 95% confidence intervals of 3.88 (1.23-16.07) and 2.66 (1.17-6.45), respectively. In the Cox propor-tional hazards model, patients carrying the ERCC1 rs11615 AA gen-otype and the XPF rs2276465 GG genotype showed only a 0.22- and 0.30-fold increased risk of death from gastric cancer. We found that the XPF rs6498486 and XPF rs2276465 polymorphisms are mark-ers of response to oxaliplatin/5-fluorouracil-based chemotherapy in gastric cancer patients.

Broustas CG, Lieberman HB
RAD9 enhances radioresistance of human prostate cancer cells through regulation of ITGB1 protein levels.
Prostate. 2014; 74(14):1359-70 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mouse embryonic stem cells null for Rad9 are sensitive to deleterious effects of ionizing radiation exposure. Likewise, integrin β1 is a known radioprotective factor. Previously, we showed that RAD9 downregulation in human prostate cancer cells reduces integrin β1 protein levels and ectopic expression of Mrad9 restores inherent high levels.
METHODS: We used RNA interference to knockdown Rad9 expression in PC3 and DU145 prostate cancer cells. These cells were then exposed to ionizing radiation, and integrin β1 protein levels were measured by immunoblotting. Survival of irradiated cells was measured by clonogenicity, cell cycle analysis, PARP-1 cleavage, and trypan blue exclusion.
RESULTS: The function of RAD9 in controlling integrin β1 expression is unique and not shared by the other members of the 9-1-1 complex, HUS1 and RAD1. RAD9 or integrin β1 silencing sensitizes DU145 and PC3 cells to ionizing radiation. Irradiation of DU145 cells with low levels of RAD9 induces cleavage of PARP-1 protein. High levels of ionizing radiation have no effect on integrin β1 protein levels. However, when RAD9 downregulation is combined with 10 Gy of ionizing radiation in DU145 or PC3 cells, there is an additional 50% downregulation of integrin β1 compared with levels in unirradiated RAD9 knockdown cells. Finally, PC3 cells growing on fibronectin display increased radioresistance. However, PC3 cells with RAD9 knockdown are no longer protected by fibronectin after treatment with ionizing radiation.
CONCLUSIONS: Downregulation of RAD9 when combined with ionizing radiation results in reduction of ITGB1 protein levels in prostate cancer cells, and increased lethality.

Sullivan I, Salazar J, Majem M, et al.
Pharmacogenetics of the DNA repair pathways in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.
Cancer Lett. 2014; 353(2):160-6 [PubMed] Related Publications
Genetic variants in DNA repair genes may play a role in the effectiveness of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). We analyzed 17 SNPs in eight genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XRCC1 and XRCC2) involved in DNA repair mechanisms and its association with outcome in NSCLC. This prospective study included patients with stages III and IV treated with platinum-based chemotherapy. All patients (n = 161) received cisplatin or carboplatin plus a third-generation drug. Additionally, stage IIIA and IIIB patients (n = 74) received concomitant or sequential radiotherapy. Germline polymorphisms were analyzed using the BioMark system in blood DNA samples. We found that in stage III patients, response was significantly associated with SNPs in ERCC1 and in ERCC3 genes, while radiotherapy-derived toxicity correlated with SNPs in the ERCC2 gene. In stage IV patients, response was associated with a genetic variant in the ERCC4 gene and survival with a SNP in the XRCC1 gene. The complexity of the DNA repair mechanisms along with the heterogeneity in the treatment of lung cancer could explain the role of multiple genes as putative biomarkers of patient outcome.

Jones RM, Kotsantis P, Stewart GS, et al.
BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine.
Mol Cancer Ther. 2014; 13(10):2412-21 [PubMed] Free Access to Full Article Related Publications
Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors.

Woodard LE, De Silva RA, Behnam Azad B, et al.
Bridged cyclams as imaging agents for chemokine receptor 4 (CXCR4).
Nucl Med Biol. 2014; 41(7):552-61 [PubMed] Free Access to Full Article Related Publications
Over-expression of chemokine receptor 4 (CXCR4) is present in a majority of cancers, has been linked to an aggressive phenotype, and may indicate the metastatic potential of primary tumor. Several CXCR4 targeted therapeutics are in clinical trials and the development of the corresponding imaging agents is an area of active interest. Previously, (64)Cu-labeled imaging agents for CXCR4 have provided clear images of CXCR4-bearing tissues in relevant experimental models but demonstrated fast washout from tissues harboring receptor. Addition of stabilizing bridges is known to provide more robust chelator-Cu(II) complexes. In addition, bridged cyclam-based CXCR4 binding agents demonstrated increased receptor residence times relative to existing agents. Based on that knowledge we synthesized several bridged cyclam analogs of AMD3465, a monocyclam-based CXCR4 imaging agent, to increase the retention time of the tracer bound to the receptor to allow for protracted imaging and improved target-to-non-target ratios. Specific accumulation of two radiolabeled, cross-bridged analogs ([(64)Cu] RAD1-24 and [(64)Cu]RAD1-52) was observed in U87-stb-CXCR4 tumors in both PET/CT imaging and biodistribution studies. At 90min post-injection of radiotracer, tumor-to-muscle and tumor-to-blood ratios reached 106.05±17.19 and 28.08±4.78, respectively, for cross-bridged pyrimidine analog [(64)Cu]RAD1-52. Receptor blockade performed in vivo denoted target binding specificity. The biodistribution and PET/CT imaging studies with the radiolabeled bridged cyclams demonstrated longer tumor retention and comparable uptake to [(64)Cu]AMD3465, though [(64)Cu]AMD3465 demonstrated superior overall pharmacokinetics.

Lee E, Levine EA, Franco VI, et al.
Combined genetic and nutritional risk models of triple negative breast cancer.
Nutr Cancer. 2014; 66(6):955-63 [PubMed] Related Publications
Triple negative breast cancer (TNBC) presents clinical challenges due to unknown etiology, lack of treatment targets, and poor prognosis. We examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. We evaluated 18 DNA-repair nonsynonymous single nucleotide polymorphisms (nsSNPs) and dietary/nutritional intakes. Multivariate Adaptive Regression Splines models were used to select nutrients of interest and define cut-off values for logistic regression models. Our results suggest that TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and β-carotene). Combined analyses of these 6 nsSNPs and 3 micronutrients showed significant association with TNBC: odds ratios = 2.77 (95% confidence interval = 1.01-7.64) and 10.89 (95% confidence interval = 3.50-33.89) for 2 and at least 3 risk factors, respectively. To the best of our knowledge, this is the first study to suggest that multiple genetic and nutritional factors are associated with TNBC, particularly in combination. Our findings, if validated in larger studies, will have important clinical implication that dietary modulations and/or micronutrient supplementations may prevent or reverse TNBC phenotype, so tumors can be treated with less toxic therapeutic strategies, particularly in genetically susceptible women.

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