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Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response. A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria. Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (CDKN1A, ERCC1, ERCC2, ERCC4, ERCC6, EXO1, MLH1, MNAT1, MUTYH, PARP4, PCNA, POLE, POLR1G, RAD23B, RFC1, RFC3, RPA1, RPA3, TREX1, UNG, XPC, XRCC1) and somatic expression (CDKN1A, PARP1, PCNA, MGMT, RECQL, RFC5) were associated with melphalan outcomes in ≥ 1 study. It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.

Genetic variants in genes involved in the distribution, metabolism, accumulation or repair of lesions are likely to influence the response of drugs used in the treatment of Head and Neck Cancer (HNC). We examine the effect of 36 SNPs on clinical outcomes in patients with locally advanced HNC who were receiving platinum-based chemoradiotherapy (CRT). These SNPs were genotyped in 110 patients using the iPLEX Gold assay on the MassARRAY method in blood DNA samples and used Kaplan–Meier and Cox regression analyses to compare genotype groups with the survival. Two SNPs, rs717620 (ABCC2) and rs12934241 (MMP2) were strongly associated with overall survival (OS) and disease-free survival (DFS). At a median follow-up of 64.4 months, the allele A of rs717620 (ABCC2) had an increased risk of disease progression {hazard ratio [HR] = 1.79, p = 0.0018} and death (HR = 2.0, p = 0.00027). ABCC2 was associated with OS after a Bonferroni adjustment for multiple testing. The MMP2 rs12934241‐T allele was associated with an increased risk of worse OS and DFS (p = 0.0098 and p = 0.0015, respectively). One SNP of ABCB1 and three SNPs located in the ERCC2 gene showed an association with response in the subgroup of HNC patients treated with definitive CRT. Our findings highlight the potential usefulness of SNPs in different genes involved in drug metabolism and repair DNA to predict the response and survival to CRT. ABCC2 is a potential predictor of OS in patients with HNC.

Bu çalışmada ileri evre mide kanserli Türk hastalarda XPD/ERCC2, RAD51 ve hOGG1 gen polimorfizminin prognoz üzerine etkisinin olup olmadığını değerlendirdik. Çalışmaya performans durumu 0-2 olan, inoperabl lokal ileri veya uzak metastazlı 31 mide kanseri hastası ile kontrol grubu olarak 29 sağlıklı birey dahil edildi. DNA serumdan izole edildikten sonra tek nükleotid gen polimorfizmi MassARRAY Analyzer 4 System [Sequenom] kullanılarak analiz edildi. Gözlenen genotip frekanslarının istatistiksel değeri beklenen genotip frekanslarına kıyasla Hardy-Weinberg kuralına göre belirlendi. Hasta grubunda ortanca yaş 68 (yıl) ve hastaların %74’ü erkek, %26’sı kadın idi. XPD/ERCC2 Asp312Asn [rs1799793] tek nükleotit gen polimorfizmi G23591A, RAD51 [rs1801320] tek nükleotit gen polimorfizmi G135C ve hOGG1 Ser 326 Cys [rs1052133] tek nükleotid gen poliforfizmi tespit edildi. Mide kanserli Türk hastalarda genotipler ile prognoz arasında anlamlı bir ilişki kuramadık., In this study, we evaluated the effects of XPD/ERCC2, RAD51 and hOGG1 gene polymorphisms on prognosis in Turkish patients with advanced gastric cancer. A total of 31 gastric cancer patients with locally inoperable or distant metastasis and performance status of 0–2 and 29 healthy volunteers as the control group were enrolled in this study. DNA was isolated from serum and then single nucleotide gene polymorphism analyses were done by MassARRAY Analyzer 4 System [Sequenom]. Statistical significance of the observed genotype frequencies was evaluated according to Hardy–Weinberg rule compared to the expected genotype frequencies. Median age was 68 years: 74% male, 26% female in the study group. We determined the XPD/ERCC2 Asp312Asn [rs1799793] single nucleotide gene polymorphism G23591A, RAD51 [rs1801320] single nucleotide gene polymorphism G135C and hOGG1 Ser 326 Cys [rs1052133] single nucleotide gene polymorphism. We could not find any significant association between the genotypes and prognosis in Turkish patients with gastric cancer.

Although the ERCC2 gene rs13181 polymorphism is involved in the pancreatic cancer pathogenic mechanism, there is no consistent finding. This meta-analysis aimed to determine the association between ERCC2 rs13181 polymorphism and pancreatic cancer. Related articles were searched against the PubMed database in a retrospective way. Additionally, the combined odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated using the random- or fixed-effects model. Altogether, seven articles regarding ERCC2 gene rs13181 polymorphism were enrolled. The combined ORs regarding the relationship of ERCC2 rs13181 polymorphism with pancreatic cancer incidence showed significant differences in each genetic model (C vs. A: OR = 1.14, 95% CI = 1.04-1.26; CC vs. AA: OR = 1.53, 95% CI = 1.24-1.90; AC vs. AA: OR = 1.06, 95% CI 0.92-1.22; recessive model: OR = 1.50, 95% CI = 1.22-1.84; dominant model: OR = 1.16, 95% CI = 1.02-1.32). Additionally, we performed subgroup analysis stratified by race, which revealed that ERCC2 rs13181 polymorphism increased the risk of pancreatic cancer in Asian populations. This work suggests that the ERCC2 gene rs13181 polymorphism is related to pancreatic cancer risk in Asians.

Previous studies have indicated that genetic variations in individuals may result in changes in gene expression and amino acids. The effect of these changes may lead to different responses to platinum-based chemotherapy. A vast response rate interval and a short survival rate indicate that the efficacy and efficiency of the selection of chemotherapy have not been optimized. This article aims to illustrate the potential relationship of various genetic polymorphisms in response to platinum-based chemotherapy for several types of cancer. This review was conducted using articles from the last three- and five-year periods (2014-2019) that use gene polymorphism and its relationship to the efficacy of platinum-based chemotherapy as their theme. A total of 26 out of 488 relevant articles were included based on specific criteria. Through various mechanisms, genes, including ERCC1, ERCC2/XPD, XPC, XPA, XRCC1, APE-1, PARP1, OGG1, ABCC2, MRP, GSTP1, GSTM1, GSTT1, MATE1, and OCT2, have been associated with patient response to platinum-based chemotherapy. We conclude that genetic polymorphism analysis is recommended for the management of cancer so that each patient can be administered therapy based on his or her genetic profile to achieve an effective and efficient outcome.

This study evaluated the prognostic value of a panel of 29 oncogenes derived from the analysis of The Cancer Genome Atlas (TCGA data) or from the recent literature on bladder tumors on a well-characterized series of muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) samples and tried to identify molecular prognostic markers. Mutations of HRAS, FGFR3, PIK3CA and TERT were found in 2.9%, 27.2%, 14.9% and 76.7% of tumor samples, respectively. Concerning NMIBC, on multivariate analysis, RXRA and FGFR3 levels were associated with recurrence-free survival (RFS) (p = 0.0022 and p = 0.0069) and RXRA level was associated with progression to muscle-invasive disease (p = 0.0068). We identified a 3-gene molecular signature associated with NMIBC prognosis. FGFR3 overexpression was associated with reduced response to Bacillus Calmette–Guerin treatment (p = 0.037). As regards MIBC, on multivariate analysis, ERCC2 overexpression was associated with RFS (p = 0.0011) and E2F3 and EGFR overexpression were associated with overall survival (p = 0.014 and p = 0.035). RT-PCR findings were confirmed by IHC for FGFR3. Genomic alterations in MIBC revealed in TCGA data also concern NMIBC and seem to be associated with prognosis in terms of recurrence and progression. Correcting these alterations by targeted therapies seems a promising pharmacological approach.

Introduction Among the Jordanian population, brain tumors are the tenth most common type of cancers in both males and females, comprising 2.8% of all newly diagnosed neoplasms. Diffuse gliomas are the most prevalent and the most aggressive primary brain tumors in adults. The incidence of diffuse gliomas varies among different populations; this variation is partially linked to genetic polymorphisms. The purpose of the study is to examine the association between (BRCA1 rs799917G>A, rs1799966T>C, EXO1 rs1047840G>A, EME1 rs12450550T>C, ERCC2 rs13181T>G, rs1799793C>T, and XRCC1 rs1799782G>A) DNA repair gene polymorphisms and glioblastoma multiforme (GBM) susceptibility, and survival in the Jordanian Arab population. Methods Eighty-four patients diagnosed with glioblastoma multiforme at the King Abdullah University Hospital (KAUH) between 2013 and 2018 and 225 healthy cancer-free control subjects with similar geographic and ethnic backgrounds to the patients were included in the study. Genomic DNA was extracted from the formalin-fixed paraffin-embedded tissues of the subjects. The Sequenom MassARRAY® sequencer system (iPLEX GOLD) was used. The analyses included assessments of population variability and survival. Results This study is the first to address the relationship between BRCA1 rs1799966 and rs799917 SNP, and the risk of GBM among the Arab Jordanian population. The findings of the study show that BRCA1 rs799917 is associated with decreased risk of GBM in the recessive model (AA vs G/G-A/G: OR, 0.46, 95% CI, 0.26-0.82, p=0.01) and the same SNP is associated with increased risk of GBM in the overdominant model (AG vs G/G-A/A: OR, 1.72, 95% CI, 1.02-2.89, p=0.04).

Background Single nucleotide polymorphisms (SNPs) in DNA repair genes have a potential clinical value in predicting treatment outcomes. In the current study, we examined the association of SNPs in the genes XRCC1-rs25487, ERCC1-rs11615, ERCC2-rs238406, and ERCC2-rs13181 with colorectal cancer (CRC) risk, relapse-free survival (RFS), overall survival (OS), and toxicity during chemotherapy. Methods SNPs were analysed in 590 CRC cases and 300 controls using TaqMan technology. The association of SNPs with CRC risk and toxicity during chemotherapy was analysed using Chi2 test. The Kaplan–Meier method and log-rank test was used to measure the effects of the SNPs on RFS and OS. Results The CC genotype of ERCC2-rs238406 and the ERCC2-rs13181 C allele were associated with a significantly increased risk of CRC. The ERCC1-rs11615 genotype T/T was associated with stomatitis in adjuvant chemotherapy (p = 0.03). Also, more patients with the ERCC2-rs13181 C allele needed dose reduction compared to patients with the A/A genotype (p = 0.02). In first line chemotherapy, more patients with the ERCC1-rs11615 C allele suffered from nausea compared to those with the T/T genotype (p = 0.04) and eye reactions and thrombocytopenia were more common in patients with the ERCC2-rs13181 C allele compared to the A/A genotype (p = 0.006 and p = 0.004, respectively). ERCC2- rs238406 C/C was also associated with a higher frequency of thrombocytopenia (p = 0.03). A shorter 5-year OS was detected in stage I & II CRC patients with the ERCC2- rs238406 C allele (p = 0.02). However, there was no significant association between the SNPs and 5-year RFS. Conclusions Both SNPs in ERCC2 were associated with risk of CRC as well as toxicity during first line treatment. In addition, ERCC2- rs238406 was linked to OS in early stage CRC. The ERCC1-rs11615 variant was associated with toxicity during adjuvant chemotherapy. The results add support to previous findings that SNPs in ERCC1 and ERCC2 have a prognostic and predictive value in clinical management of CRC.

Purpose Genetic variations in DNA damage repair (DDR) genes may influence radiation therapy (RT)–induced acute normal tissue toxicity in patients with breast cancer. Identifying an individual or multiple single-nucleotide polymorphisms (SNPs) associated with RT–induced early adverse skin reactions (EASR) is critical for precision medicine in radiation oncology. Methods and Materials At the completion of RT, EASR was assessed using the Oncology Nursing Society scale (0-6) in 416 patients with breast cancer, and Oncology Nursing Society score ≥4 was considered RT-induced EASR. PLINK set-based tests and subsequent individual SNP association analyses were conducted to identify genes and SNPs associated with EASR among the 53 DDR genes and 1968 SNPs. A weighted polygenic risk score (PRS) model was constructed to ascertain the association between the joint effect of risk alleles and EASR. Results The study population consisted of 264 Hispanic whites, 86 blacks or African Americans, 55 non-Hispanic whites, and 11 others. A total of 115 patients (27.6%) developed EASR. Five genes (ATM, CHEK1, ERCC2, RAD51C, and TGFB1) were significantly associated with RT-induced EASR. Nine SNPs within these 5 genes were further identified: ATM rs61915066, CHEK1 rs11220184, RAD51C rs302877, rs405684, TBFB1 rs4803455, rs2241714, and ERCC2 rs60152947, rs10404465, rs1799786. In a multivariable-adjusted PRS model, patients in a higher quartile of PRS were more likely to develop EASR compared with patients in the lowest quartile (ORq2 vs.q1 = 1.94, 95% CI, 0.86-4.39; ORq3 vs.q1 = 3.46, 95% CI, 1.57-7.63; ORq4 vs.q1 = 8.64, 95% CI, 3.92-19.02; and Ptrend Conclusions We newly identified the associations between 9 SNPs in ATM, CHEK1, RAD51C, TGFB1, and ERCC2 and RT-induced EASR. PRS modeling showed its potential in identifying populations at risk. Multiple SNPs in DDR genes may jointly contribute to interindividual variation in RT-induced EASR. Validation in an independent external cohort is required to determine the clinical significance of these predictive biomarkers.

This study aimed to determine the main single nucleotide polymorphisms (SNPs) that are associated with an increased or decreased risk of glioma development in healthy individuals. We conducted a systematic review of the articles published in English on the PUBMED database between January 2008 and December 2017. Our search resulted in a total of 743 articles; however, only 56 were included in this review. A total of 148 polymorphisms were found, which involved 64 different genes. The polymorphisms that were most associated with an increased risk of glioma development were polymorphic variants rs179782, rs13181, and rs3791679 of the genes XRCC1, ERCC2, and EFEMP1, respectively.

Results from studies in several cancers on single nucleotide polymorphisms (SNPs) suggest that DNA repair capacity may have prognostic implication for disease recurrence, survival, and responses to treatment. This study aimed to evaluate the potential prognostic value of SNPs as biomarkers in patients with metastatic non-small cell lung cancer (mNSCLC) treated with platinum. Analysis of SNPs from peripheral blood cells was performed by polymerase chain reaction. Excision repair cross-complementing group 1 (ERCC1)-Asn118Asn, excision repair cross-complementing group 2 (ERCC2)-Lys751Gln, X-ray repair cross-complementing group 1 (XRCC1)-Arg399Gln, and tumor protein 53 (TP53)-Arg72Pro polymorphisms were evaluated in conjunction with clinical and pathological parameters, and survival. The median progression-free survival (PFS) and overall survival (OS) of 145 patients were 5.1 months and 30.9 months, respectively. In the univariate analysis ERCC1 genotype, XRCC1 genotype, and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) were significant parameters for OS. In the multivariate analysis ERCC1 genotype, XRCC1 genotype, and ECOG-PS retained their significance. The median OS was 45.2 months for the ERCC1 normal (CC) and heterozygote (CT) genotypes, and 25.5 months for the ERCC1 mutant (TT) genotype. The median OS was 31.4 months for the XRCC1 normal (AA) and heterozygote (AG) genotypes, and 23.1 months for the XRCC1 mutant (GG) genotype. The median OS was 30,7 months for ECOG-PS≤ 1 and 10.2 months for ECOG-PS≥ 2. ERCC1 and XRCC1 genotypes, and ECOG-PS independently predicted OS in mNSCLC patients. Additional studies are needed for the further evaluation of potential prognostic SNPs in mNSCLC. [Med-Science 2020; 9(1.000): 255-60]

Background: The relationship between ERCC gene polymorphism and osteosarcoma risk / overall survival of osteosarco- ma is still conflicting, and this meta-analysis was performed to assess these associations. Material and methods: The association studies were identified from PubMed, and eligible reports were included and cal- culated using meta-analysis method. Results: Four studies were included for the association of ERCC gene polymorphism with osteosarcoma risk, and nine studies were recruited into this meta-analysis for the relationship between ERCC gene polymorphism and overall survival of osteosarcoma. The meta-analysis indicated that ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (A>G) gene polymorphism, ERCC2 rs13181 (Lys751Gln) gene pol- ymorphism were not associated with osteosarcoma risk. ERCC1 rs2298881 (C>A) gene polymorphism, ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (Asp312Asn) gene polymorphism were not associated with overall survival of osteosarcoma. Interestingly, ERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma, but AA genotype not (A allele: OR = 0.78, 95% CI: 0.65- 0.93, P = 0.007; GG genotype: OR = 1.32, 95% CI: 1.05-1.65, P = 0.02; AA genotype: OR = 0.69, 95% CI: 0.45-1.04, P = 0.08). Conclusion: ERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma. Keywords: Osteosarcoma; overall survival of osteosarcoma; ERCC; gene polymorphism; meta-analysis.

Background. Improving the osteosarcoma (OS) patients’ survival has long been a challenge, even though the disease’s treatment is on the verge of progress. DNA damage response (DDR) has traditionally been associated with carcinogenesis, tumor growth, and genomic instability. No study has used DDR genes as a signature to identify the prognosis of OS. The goal of this work was to find an effective possible DDR gene biomarker for predicting OS prognosis, which may be useful in clinical diagnosis and therapy. Methods. To assess gene methylation, univariate and multivariate cox regression analyses were performed on data from OS patients. The data were retrieved from public databases, including the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and the Gene Expression Omnibus (GEO). Results. The DDR gene signature was chosen, which included seven genes (NHEJ1, RMI2, SWI5, ERCC2, CLK2, POLG, and MLH1). In the TARGET dataset, patients were categorized into two groups: high-risk and low-risk. Patients with a high-risk score revealed a shorter OS rate (hazard ratio (HR): 3.15, 95% confidence interval (CI): 1.38–4.34, P < 0.001 ) in comparison with the patients with a low-risk score in the TARGET as a training group. The validation of the prognostic signature accuracy was carried out in relapse and validation cohorts (TARGET, n = 75; GSE21257, n = 53). The signature was found to be an independent predictive factor for OS in multivariate cox regression analysis, and a nomogram model was developed to predict an individual’s risk of OS. DDR gene signature involved in Fanconi anemia pathway, nonhomologous end−joining pathway, mismatch repair, and nucleotide excision repair pathway. Conclusions. Our study suggests that the identified novel DDR genes could be a powerful prognostic tool for prognosis evaluation and a valuable tool in predicting the risk factors in OS patients.

Normal tissue radiosensitivity is thought to be influenced by an individual’s genetic background. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2–3 subcutaneous fibrosis and/or grade 2–3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance (p &lt, 0.05). In the replication study, which consisted of an additional 45 cases and 192 controls, none of the SNVs identified by targeted NGS achieved nominal replication. Nevertheless, TP53 rs1042522 (G &gt, C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82–2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51–14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06–3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients, however, large replication studies are warranted for conclusive evidence.

In following study we examined whether blood arsenic (As) levels combined with specific polymorphisms in MT1B, GSTP1, ABCB1, NQO1, CRTC3, GPX1, SOD2, CAT, XRCC1, ERCC2 can be used as a marker for the detection of colorectal cancer (CRC) among Polish women. A retrospective case-control study of CRC included 83 CRC cases and 78 healthy controls. From each study participant pre-treatment peripheral blood was collected for As level measurement by inductively coupled–plasma mass spectrometry (ICP-MS). We estimated the odds ratio (OR) of the association between blood-As levels and CRC using multivariable unconditional logistic regression models. A low blood-As level (0.27–0.67 µg/L) was associated with an increased frequency of CRC (OR: 3.69; p = 0.005). This correlation was significantly greater when participants carried particular gene variants: CAT, rs1001179-nonCC (OR: 19.4; p = 0.001); ABCB1 rs2032582–CC (OR: 14.8; p = 0.024); GPX1 rs1050450-CC (OR: 11.6; p = 0.002) and CRTC3 rs12915189-nonGG (OR: 10.3; p = 0.003). Our study provides strong evidence that low blood-As levels are significantly associated with increased CRC occurrence and that particular gene variants significantly enhanced this correlation however, due to the novelty of these findings, we suggest further validation before a definitive statement that the combined effect of low blood-As levels with specific gene polymorphisms is a suitable CRC biomarker.

Background Patients with lung cancer (LC) have a poor quality of life (QoL) and easily suffer from psychological diseases. Previous studies focused less on the relationship between genetic factors and QoL, depression, and anxiety status in LC patients. The current study is intended to explore the relationship between SNPs and haplotypes of ERCC1 and ERCC2 and the QoL, depression and anxiety status of patients with LC. Methods QoL, depression and anxiety status were assessed in 291 LC patients using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), SDS and SAS. Nine tag SNPs of ERCC1 and ERCC2 were detected using an improved multiplex ligation detection reaction (iMLDR) technique. Haplotype analysis was conducted using the software Haploview 4.2. The association between SNPs or haplotypes and QoL or depression or anxiety in LC patients was analyzed by regression analysis. Results ERCC1 rs11615 was associated with emotional functioning (P = 0.027), and ERCC1 rs3212986 was associated with anxiety scores (P = 0.018). ERCC1 rs762562-rs3212986 haplotype was associated with cognitive function (P = 0.029), somatic function (P = 0.014) and dysphagia (OR = 3.32, P = 0.044). Patients with ERCC1 rs3212986-rs11615 AG haplotype had worse cognitive function (adjusted Beta = − 5.42) and somatic function (adjusted Beta = − 6.55) and had severer symptoms of loss of appetite (adjusted OR = 1.67) and dysphagia (adjusted OR = 4.43) (All adjusted P P = 0.035), pain at other sites (OR 1.88, P = 0.014), chest pain (OR 0.42, P = 0.02), dysphagia (OR 2.82, P = 0.048), and anxiety status (OR 0.23, P = 0.009). Conclusion After adjustment for environmental factors, SNPs and haplotypes of ERCC1 and ERCC2 were associated with different domains of QoL, depression and anxiety in LC patients.

Purpose. Associations between XRCC1, XRCC3, and ERCC2 gene polymorphism and prognosis have been investigated in several cancers. The aim of this meta-analysis was to assess the prognostic value of XRCC1, XRCC3, and ERCC2 gene polymorphism in hepatocellular carcinoma (HCC). Methods. A systematic literature search was performed to identify relevant studies in PubMed, Embase, and the Cochrane library up to December 2018. The prognostic values of XRCC1, XRCC3, and ERCC2 polymorphisms in HCC were estimated using crude HRs with 95% CIs. Results. Ten studies involving 2687 patients were included in the quantitative analysis. There were no statistically significant associations between XRCC1 rs1799782 C>T, XRCC1 rs25487 G>A, and ERCC2 rs1799793 G>A polymorphisms and overall survival (OS). OS was significantly longer for the ERCC2 rs13181 CC genotype than for AA (CC vs. AA: HR = 0.33, 95% CI = 0.15–0.72). A significantly lower OS was observed for patients with the CT genotype compared with the CC genotype at XRCC3 rs861539 (CT vs. CC: HR = 1.64, 95% CI = 1.11–2.42). Conclusion. The ERCC2 rs13181 A>C polymorphism and XRCC3 rs861539 C>T polymorphism may be predictive markers for prognosis in patients with HCC. Well-designed studies with larger sample sizes are needed to verify our findings.

International audience; We examined whether 66 germline single-nucleotide polymorphisms (SNPs) in 10 candidate genes would predict clinical outcome in 316 patients with resectable locally advanced rectal cancer (LARC) enrolled in the ACCORD-12 phase III trial who were randomly treated with preoperative radiotherapy plus capecitabine (CAP45; n = 155) or dose-intensified radiotherapy plus capecitabine and oxaliplatin (CAPOX50; n = 161). The primary endpoint was tumor response according to the Dworak score. Multivariate logistic regression models adjusted on treatment arm and T stage determined the SNPs prognostic and predictive values for tumor response. In univariate analysis, five SNPs in ERCC2, XPA, MTHFR and ERCC1 were associated with the Dworak score in the CAPOX50 arm. In the overall population, interaction with treatment arm was significant for ERCC2 rs1799787 (pinteraction = 0.05) and XPA rs3176683 (pinteraction = 0.008), suggesting a predictive effect for response to oxaliplatin-based chemoradiotherapy (CRT). All but XPA rs3176683 had a prognostic effect on tumor response. In a multivariate model, interaction remained significant for XPA rs3176683 ([OR 7.33, 95% CI 1.40-38.23], pinteraction = 0.018) and the prognostic effect significant for ERCC2 rs1799787 ([OR 0.55, 95%CI 0.32-0.93], p = 0.027) and ERCC1 rs10412761 ([OR 0.57, 95%CI 0.34-0.98], p = 0.042). Patients with the T/G haplotype of rs1799787 and rs10412761 had a 60% decrease in odds of response (p

The dismal outcome in patients with locally advanced or metastatic gastric cancer (GC) highlights the need for effective systemic neoadjuvant chemotherapy to improve clinical results. This study evaluated the correlation between the expression of three DNA repair genes, namely the excision repair cross-complementing group 1 (ERCC1), excision repair cross-complementing group 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1) and the clinical outcome of patients with locally advanced or metastatic GC treated with mFOLFOX-4 neoadjuvant chemotherapy. Fifty-eight patients with histologically confirmed locally advanced or metastatic GC following neoadjuvant mFOLFOX-4 chemotherapy were enrolled between January 2009 and January 2018. We analyzed clinicopathological features and ERCC1, ERCC2, and XRCC1 expression to identify potential predictors of clinical response. Among the 58 patients, 16 (27.6%) were categorized into the response group (partial response) and 42 into the nonresponse group (stable disease in 24 patients and progressive disease in 18 patients). A multivariate analysis showed that ERCC1 overexpression (P = 0.003), ERCC2 overexpression (P = 0.049), and either ERCC1 or ERCC2 overexpression (P = 0.002) were independent predictors of response following mFOLFOX-4 neoadjuvant chemotherapy. Additionally, ERCC1 and ERCC2 overexpression did not only predict the response but also progression-free survival (both P < 0.05) and overall survival (both P < 0.05). ERCC1 and ERCC2 overexpression are promising predictive biomarkers for patients with locally advanced or metastatic GC receiving neoadjuvant mFOLFOX-4 chemotherapy and the potential clinical implication is mandatory for further investigation.

Background: Understanding to what extent a breast tumor's genetic composition may change over the course of a few months of neoadjuvant therapy has implications for optimal therapeutic approach. However, genomic changes observed across treatment may result from either treatment-induced clonal evolution or geographically disparate sampling of a heterogeneous tumor. We sought to characterize the geographic heterogeneity in primary breast tumors, and to incorporate this information into analysis of clonal evolution with neoadjuvant therapy. Methods: We assembled the largest cohort to date of multi-region (n=2-3) whole-exome sequenced (WES) or whole-genome sequenced untreated primary breast tumors with matched normal and adequate tumor purity for analysis: four tumors with data generated for this study and five tumors compiled from three previous studies. We also generated the first cohort of multi-region (n=2-6) WES breast tumors post-neoadjuvant HER2-targeted therapy and chemotherapy, sequencing one region from a pre-treatment diagnostic specimen, multiple regions from the post-treatment surgical specimen, and matched normal for five HER2+ breast tumors that did not achieve a pathologic complete response. We used an agent-based model of spatial tumor growth to investigate whether the mutational patterns we observed with treatment were consistent with pre-existing heterogeneity or treatment-induced selection. Results: In untreated primary breast tumors, on average 30% (range 1-70%) of apparently clonal mutations from a single region were absent or rare in a second, spatially disparate region (high-frequency regional, or HFR). Intra-tumor heterogeneity was similar post-treatment (HFR 28%, range 10-54%), and was higher in breast tumors than in previously analyzed colon, brain, lung, and esophageal tumors. Simulation studies confirmed that with high heterogeneity as observed in breast tumors, analysis of one pre-treatment and one post-treatment region could not distinguish treatment-induced clonal evolution from pre-existing heterogeneity; however, obtaining at least two post-treatment regions allowed for detection of clonal shifts with treatment. Analysis of multi-region data revealed that clonal replacement occurred with neoadjuvant therapy in two of the five tumors. Candidate causes of therapeutic resistance included amplifications in CCND1, ERBB4, and MYC in one subclone, and functional protein-altering mutations in ERCC2, SMO, and WT1 in another. Mathematical modeling suggested that these putative resistant subclones comprised 0.02-12.5% of the overall pre-treatment cell population, substantially larger than previous estimates of resistant tumor clone size. Conclusions: WES data from multiple regions of untreated and treated primary breast tumors revealed considerable heterogeneity that remained present throughout treatment with chemotherapy and HER2-targeted therapy, even while major clonal sweeps took place in a minority of tumors. Obtaining at least two samples for analysis from breast tumors post-neoadjuvant therapy may reveal the tumor's evolutionary path and, especially as increasing numbers of molecular and immune therapeutic targets are identified, inform new clinical strategies. Citation Format: Caswell-Jin JL, McNamara K, Reiter JG, Sun R, Hu Z, Ma Z, Suarez CJ, Tilk S, Raghavendra A, Forte V, Chin S-F, Bardwell H, Provenzano E, Caldas C, Lang J, West R, Tripathy D, Press MF, Curtis C. Clonal evolution and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-01.

Purpose: DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. Experimental Design: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene, and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile ERCC2 mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first ERCC2-deficient bladder cancer preclinical model for studying the impact of ERCC2 loss of function. Results: We used our functional assay to test the NER capacity of clinically observed ERCC2 mutations and found that most ERCC2 helicase domain mutations cannot support NER. Furthermore, we show that introducing an ERCC2 mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model. Conclusions: Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer. See related commentary by Grivas, p. 907

Background: Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA damage response genes (DDRG) can predict the response to CBC. The value of DDRG expression as a marker of CBC treatment effect remains unclear. Material and methods: RNA expression of the nine key DDRG (BCL2, BRCA1, BRCA2, ERCC2, ERCC6, FOXM1, RAD50, RAD51, and RAD52) was assessed by qRT-PCR in a cohort of 61 MICB patients (median age 66 y, 48 males, 13 females) who underwent radical cystectomy in a tertiary care center. The results were validated in the The Cancer Genome Atlas (TCGA) cohort of MIBC (n = 383). Gene expression was correlated with disease-free survival (DFS) and overall survival (OS). Subgroup analyses were performed in patients who received adjuvant cisplatin-based chemotherapy (ACBC) (Mannheim n = 20 and TCGA n = 75). Results: Low expression of RAD52 was associated with low DFS in both the Mannheim and the TCGA cohorts (Mannheim: p = 0.039, TCGA: p = 0.017). This was especially apparent in subgroups treated with ACBC (Mannheim: p = 0.0059, TCGA: p = 0.012). Several other genes showed an influence on DFS in the Mannheim cohort (BRCA2, ERCC2, FOXM1) where low expression was associated with poor DFS (p &lt, 0.05 for all). This finding was not fully supported by the data in the TCGA cohort, where high expression of FOXM1 and BRCA2 correlated with poor DFS. Conclusion: Low expression of RAD52 correlated with decreased DFS in the Mannheim and the TCGA cohort. This effect was especially pronounced in the subset of patients who received ACBC, making it a promising indicator for response to ACBC on the level of gene expression.

Simple Summary In cancer cells, the DNA repair response can be exploited as an ‘Achilles heel’ to trigger programmed cell death pathways and tumor elimination. Rather than involving ‘naked’ DNA, repair occurs in the context of histone and non-histone proteins in the vicinity of the damage. Drugs that target different epigenetic mechanisms can lead to the synergistic downregulation of critical DNA repair factors, including those associated with poor survival in colorectal cancer patients. Notably, normal colonic epithelial cells are more resistant than colon cancer cells to the epigenetic drug combinations. In the current investigation, cell-based assays and preclinical animal models reaffirmed the crosstalk between DNA repair and epigenetic regulatory mechanisms, and provided new avenues for precision oncology and cancer interception. Abstract There is growing evidence that DNA repair factors have clinical value for cancer treatment. Nucleotide excision repair (NER) proteins, including excision repair cross-complementation group 2 (ERCC2), play a critical role in maintaining genome integrity. Here, we examined ERCC2 expression following epigenetic combination drug treatment. Attention was drawn to ERCC2 for three reasons. First, from online databases, colorectal cancer (CRC) patients exhibited significantly reduced survival when ERCC2 was overexpressed in colon tumors. Second, ERCC2 was the most highly downregulated RNA transcript in human colon cancer cells, plus Ercc2 in rat tumors, after treatment with the histone deacetylase 3 (HDAC3) inhibitor sulforaphane (SFN) plus JQ1, which is an inhibitor of the bromodomain and extraterminal domain (BET) family. Third, as reported here, RNA-sequencing of polyposis in rat colon (Pirc) polyps following treatment of rats with JQ1 plus 6-methylsulfinylhexyl isothiocyanate (6-SFN) identified Ercc2 as the most highly downregulated gene. The current work also defined promising second-generation epigenetic drug combinations with enhanced synergy and efficacy, especially in metastasis-lineage colon cancer cells cultured as 3D spheroids and xenografts. This investigation adds to the growing interest in combination approaches that target epigenetic ‘readers’, ‘writers’, and ‘erasers’ that are deregulated in cancer and other pathologies, providing new avenues for precision oncology and cancer interception.

Everolimus monotherapy use for metastatic renal cell carcinoma (mRCC) has diminished due to recent approvals of immune checkpoint and VEGF inhibitors. We hypothesized that gene expression associated with everolimus benefit may provide rationale to select appropriate patients. To address this hypothesis, tumors from a phase I/II trial that compared everolimus alone or with BNC105P, a vascular disrupting agent, were profiled using Nanostring as a discovery cohort. A phase III trial (CheckMate 025) was used for validation. Clinical benefit (CB) was defined as response or stable disease for ≥6 months. A propensity score covariate adjustment was used, and model discrimination performance was assessed using the area under the ROC curve (AUC). In a discovery cohort of 82 patients, 35 (43%) were treated with everolimus alone and 47 (57%) received everolimus + BNC105P. Median PFS (mPFS) was 4.9 (95% CI, 2.8–6.2) months. A four-gene signature (ASXL1, DUSP6, ERCC2, and HSPA6) correlated with CB with everolimus ± BNC105P [AUC, 86.9% (95% CI, 79.2–94.7)]. This was validated in 130 patients from CheckMate 025 treated with everolimus [AUC, 60.2% (95% CI, 49.7–70.7)]. Among 43 patients (52.4%) with low expression of an 18-gene signature, everolimus + BNC105P was associated with significantly longer mPFS compared with everolimus alone (10.4 vs. 6.9 months; HR, 0.49; 95% CI, 0.24–1.002; P = 0.047). These signatures warrant further validation to select patients who may benefit from everolimus alone or with a vascular disrupting agent.

Purpose: Nucleotide excision repair (NER) gene alterations constitute potential cancer therapeutic targets. We explored the prevalence of NER gene alterations across cancers and putative therapeutic strategies targeting these vulnerabilities. Experimental Design: We interrogated our institutional dataset with mutational data from more than 40,000 patients with cancer to assess the frequency of putative deleterious alterations in four key NER genes. Gene-edited isogenic pairs of wild-type and mutant ERCC2 or ERCC3 cell lines were created and used to assess response to several candidate drugs. Results: We found that putative damaging germline and somatic alterations in NER genes were present with frequencies up to 10% across multiple cancer types. Both in vitro and in vivo studies showed significantly enhanced sensitivity to the sesquiterpene irofulven in cells harboring specific clinically observed heterozygous mutations in ERCC2 or ERCC3. Sensitivity of NER mutants to irofulven was greater than to a current standard-of-care agent, cisplatin. Hypomorphic ERCC2/3-mutant cells had impaired ability to repair irofulven-induced DNA damage. Transcriptomic profiling of tumor tissues suggested codependencies between DNA repair pathways, indicating a potential benefit of combination therapies, which were confirmed by in vitro studies. Conclusions: These findings provide novel insights into a synthetic lethal relationship between clinically observed NER gene deficiencies and sensitivity to irofulven and its potential synergistic combination with other drugs. See related commentary by Jiang and Greenberg, p. 1833

Oral cancer is the fourth most common type of cancer among males in Taiwan, and the prognosis for patients with advanced-stage oral squamous cell carcinoma (OSCC) remains poor. The present study investigated the prognostic value of three DNA repair genes, namely excision repair cross-complementing group 1 (ERCC1), ERCC2 and X-ray repair cross-complementing group 1 (XRCC1) in OSCC. The protein expression levels of XRCC1, ERCC1 and ERCC2 in oral cell lines were analyzed via western blotting and immunohistochemistry using samples from 98 patients with biopsy-proven OSCC, while the χ2 test was used to analyze the clinicopathological association. Kaplan-Meier estimates were used to determine the prognostic value of XRCC1, ERCC1 and ERCC2 for overall survival, and the log-rank test was used to evaluate the significance of differences. Multivariate analysis revealed a positive association between ERCC2 expression and OSCC recurrence (19.64-fold; 95% CI, 5.00-77.1; P

High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non–muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analyses were performed, focusing on 95 genes known to be mutated in bladder cancer. Somatic mutations, copy-number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Tumor mutational burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients (P = 0.017). DNA damage response gene mutations were associated with higher TMB (P < 0.0001) and GO (P = 0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R (P = 0.047; P = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO (P = 0.047; P = 0.0002). pT1b microstaging was associated with a genomic cluster (P = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. Significance: Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.

Purpose: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases. Experimental Design: We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity. Results: We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models. Conclusions: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven. See related commentary by Jiang and Greenberg, p. 1833

BackgroundGliomas are the most common primary tumors of the central nervous system with unclear etiology, however hereditary factors may play important roles in the development of gliomas with mutations and single nucleotide polymorphisms (SNPs) being prominent among the genetic changes. this systematic review and meta-analysis assess the association of XRCC1 (rs1799782) and ERCC2 (rs13181) gene polymorphisms and glioma risk.MethodsThis study included articles indexed in the PUBMED and EMBASE databases published during the past 15 years. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The PICOS model was used to develop the inclusion criteria and search terms. This review was recorded at PROSPERO International prospective register of systematic reviews, ID 196173. The META-MAR V2.7.0 meta-analysis calculator was used for the statistical analysis with p-values < 0.05 being considered statistically significant. Dichotomous data are presented as odds ratios (OR) with a 95% confidence interval (CI). Statistical heterogeneity was measured using the I2 test and I2 > 50% were regarded as high heterogeneity. Funnel plots, Begg (BT) and Egger Tests (ET) were used to assess publication bias (pResults Literature review identified 10 articles on ERCC2 gene rs13181 variant and 11 on XRCC1 rs1799782. The meta-analysis identified a risk for gliomas for the TT genotype of the XRCC1 rs1799782 SNP in Asians (OR: 1.59, 95% CI: 1.3-1.93; p=0.006; I2 13.1%). ERCC2 rs13181 polymorphisms identified as risks for gliomas were AC genotypes in Asians (OR: 2.06, 95% CI: 1.75-1.42; p = 0.00057; I2 91.1%) and Caucasians (OR: 1.16, 95% CI: 1.01-1.31; p = 0.02; I2 12.2%), and CC genotypes in Caucasians (OR: 2.06, 95% CI: 1.75-1.42; p = 0.0001; I2 98.9%).Conclusions TT genotypes of the XRCC1 rs1799782 SNP in Asians, AC genotypes of ERCC2 rs13181 polymorphisms in Asians and Caucasians, and CC genotypes of ERCC2 rs13181 polymorphisms in Caucasians were associated with increased risk for gliomas that may benefit these patients with early diagnostic and therapeutic strategies.

Alternative splicing (AS) events were reportedly associated with the development of multiple cancers. The study was designed to provide a comprehensive analysis of AS events and explore their potential prognostic value in uveal melanoma (UM). The prognostic AS events, identified based on the data of 80 UM patients obtained from The Cancer Genome Atlas, were further screened and analyzed for construction of prognostic signatures by using LASSO regression and multivariate Cox model. Kaplan–Meier survival analysis was used to evaluate the prognostic value. The AS events-related functional pathways were explored by gene set enrichment analysis (GSEA). The difference between two subgroups in terms of treatment options was investigated. The regulatory network between prognostic AS events and splicing factors (SFs) was then constructed. A total of 1014 AS events were identified as prognostic AS events. Five prognostic AS events were involved in the construction of prognostic signatures, including AKAP2/87175/AP, RGMA/32575/ES, DNASE1L1/90581/ES, BIN1/55198/ES and ERCC2/50430/AT. UM patients were then divided into two subgroups. Prognostic AS signatures had an excellent performance in predicting the survival of UM patients, with an area under curve (AUC) of 0.962. GSEA results suggested several splicing-associated mechanisms, including cellular metabolic process and apoptosis. Low-risk subgroup could be more sensitive to drugs. A higher expression of immune checkpoint genes was observed in high-risk group than in low-risk group. SFs-AS regulatory network also revealed significant association between AS events and SFs. Aberrant AS events in UM patients might serve as prognostic predictors.

Genomic profiling of tumors enables therapeutic decisions, and identifying drug-matched mutations will prolong survival and prognosis. Here, we generated a custom panel for detecting genetic alterations in 19 patients with urothelial bladder cancer. This panel targeted 71 genes associated with urological cancer. Targeted sequencing was performed on formalin-fixed paraffin-embedded tumor tissues. Paired patient-matched tumor and blood samples were subjected to this analysis. A total of 142 somatic mutations were detected in 19 tumor tissues. At least one non-synonymous mutation was detected in all tumor tissues, and KDM6A, KMT2D, TP53, KMT2C, PIK3CA, and ERCC2 were recurrently mutated. Chromatin remodeling and epigenetic modifier genes are frequently mutated. Of 142 mutations, 69 mutations (49%) were annotated to have oncogenic potential. Furthermore, 74% of patients were expected to receive targeted therapy due to drug-matched mutations being identified in their tumors. Among this cohort, a patient harbored an ERCC2 helicase domain mutation and would be expected to respond to platinum-based therapy. As expected, the patient received carboplatin-containing neoadjuvant therapy with a remarkable response. Furthermore, tumor-derived mutations in urine were rapidly decreased after neoadjuvant therapy. These results suggested targeted sequencing could help to detect drug-matched somatic mutations and indicate single or combination therapy for cancer patients.

Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age.

Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234–0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177–3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.

Lu Yang,1,* Ming Xu,2,* Chuan-Bao Cui,1 Peng-Hai Wei,1 Shu-Zhi Wu,1 Zuo-Jie Cen,1 Xing-Xing Meng,1 Qiong-Guang Huang,1 Zhi-Chun Xie1 1Department of Epidemiology, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Human Anatomy and Histology and Embryology, Qilu Medical University, Zibo 255213, Shandong Province, People’s Republic of China *These authors contributed equally to this work Background: The current study aims at using the whole genome expression profile chips for systematically investigating the diagnostic and prognostic values of excision repair cross-complementation (ERCC) genes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).Materials and methods: Whole genome expression profile chips were obtained from the GSE14520. The receiver-operating characteristic (ROC) curve, survival analysis, and nomogram were used to investigate the diagnostic and prognostic values of ERCC genes. Investigation of the potential function of ERCC8 was carried out by gene set enrichment analysis (GSEA) and genome-wide coexpression analysis.Results: ROC analysis suggests that six ERCC genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC8) were dysregulated and may have potential to distinguish between HBV-related HCC tumor and paracancerous tissues (area under the curve of ROC ranged from 0.623 to 0.744). Survival analysis demonstrated that high ERCC8 expression was associated with a significantly decreased risk of recurrence (adjusted P=0.021; HR=0.643; 95% CI=0.442–0.937) and death (adjusted P=0.049; HR=0.631; 95% CI=0.399–0.998) in HBV-related HCC. Then, we also developed two nomograms for the HBV-related HCC individualized prognosis predictions. GSEA suggests that the high expression of ERCC8 may have involvement in the energy metabolism biological processes. As the genome-wide coexpression analysis and functional assessment of ERCC8 suggest, those coexpressed genes were significantly enriched in multiple biological processes of DNA damage and repair. Conclusion: The present study indicates that six ERCC genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC8) were dysregulated between HBV-related HCC tumor and paracancerous tissues and that the mRNA expression of ERCC8 may serve as a potential biomarker for the HBV-related HCC prognosis. Keywords: HBV, hepatocellular carcinoma, diagnosis, prognosis, ERCC

BACKGROUND The objective of this study was to detect the association between ERCC excision repair 2, TFIIH core complex helicase subunit (ERCC2) gene polymorphisms and diffuse large B-cell lymphoma (DLBCL) susceptibility. MATERIAL AND METHODS This study used a case-control design. ERCC2 gene rs1799793 (Asp312Asn) and rs13181 (Lys751Gln) polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) both in DLBCL patients and healthy controls. The association between ERCC2 gene polymorphisms and DLBCL risk was assessed by χ² test. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were used to address the association strength. Subgroup analyses were also performed to investigate the genetic effects of ERCC2 polymorphisms on clinical characteristics of DLBCL patients. RESULTS A significant association was discovered between the rs1799793 A allele and increased DLBCL risk (P=0.031, OR=1.928, 95% CI=1.052-3.534). The C allele of rs13181 was obviously associated with elevated DLBCL susceptibility (P=0.047, OR=1.820, 95% CI=1.002-3.305). The subgroup analysis demonstrated that rs1799793 and rs13181 polymorphisms had no relationship with serum lactate dehydrogenase level, nidus number, B-symptoms, Ann Arbor stages, or immunological types in DLBCL cases (P>0.05 for all). CONCLUSIONS Minor allele carriers of ERCC2 gene rs1799793 (Asp312Asn) and rs13181 (Lys751Gln) polymorphisms had higher susceptibility to DLBCL.

Epidemiological studies have assessed the association between excision repair cross-complementing group 2 (ERCC2) Lys751Gln and Asp312Asn polymorphisms and melanoma risk with conflicting results. Relevant articles were searched from PubMed, Embase, and Web of Science with a time limit of 3 September 2016. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. We performed this meta-analysis with 12 studies including 6157 cases and 8873 controls for Lys751Gln and nine studies including 5037 cases and 7542 controls for Asp312Asn polymorphism. Overall, no significant associations were found under all the models for Lys751Gln polymorphism, and significant associations were found for Asp312Asn polymorphism for AA versus GG (OR=1.12, 95% CI=1.00-1.26) and for the recessive model (OR=1.11, 95% CI=1.00-1.24). In the stratification analyses by source of control: for Lys751Gln polymorphism, significant associations were found for CC versus AA (OR=1.19, 95% CI=1.04-1.36) and the recessive model (OR=1.15, 95% CI=1.02-1.30); for Asp312Asn polymorphism, significant associations were found for AA versus GG (OR=1.31, 95% CI=1.11-1.53) and the recessive model (OR=1.29, 95% CI=1.11-1.50). This meta-analysis suggested that both the Lys751Gln and Asp312Asn polymorphisms were risk factors for melanoma risk in population-based subgroup.

Purpose Some previous studies have sought to investigate the roles of excision repair cross complementation group 1 (ERCC1), ERCC2, ERCC4, and ERCC5 gene polymorphisms in the prognosis of osteosarcoma patients. However, their results were inconclusive. Here, we performed a meta-analysis to determine the strength of the association between eight polymorphisms in the ERCC genes (rs11615, rs3212986, rs2298881, rs13181, rs1799793, rs1800067, rs2296147, and rs1047768) and prognosis of osteosarcoma patients treated with chemotherapy. Materials and methods We retrieved the relevant studies from PubMed, Embase, and Web of Science in human osteosarcoma published prior to July 2017. Primary outcomes included overall survival (OS) and event-free survival, expressed by hazard ratios (HRs) with their corresponding 95% CIs. STATA software (version 12.0) was utilized to perform data synthesis. Results A total of 13 eligible follow-up studies involving 2,303 patients met all the inclusion criteria, conducted in two populations of ethnic descent: 11 Asians and two Caucasians. In the present meta-analysis, we demonstrated that the homozygous variant genotypes in ERCC2 rs1799793 and ERCC5 rs2296147 were significantly associated with OS in osteosarcoma (TT vs GG for rs1799793: HR = 0.62, 95% CI = 0.41-0.93, Pheterogeneity = 0.310, I2 = 15.3%, P = 0.020; TT vs CC for rs2296147: HR = 0.42, 95% CI = 0.23-0.78, Pheterogeneity = 0.708, I2 = 0.0%, P = 0.006). In addition, no evidence of association was observed between prognosis in osteosarcoma and ERCC1 rs11615, ERCC1 rs3212986, ERCC1 rs2298881, ERCC2 rs13181, ERCC4 rs1800067, and ERCC5 rs1047768 polymorphisms. Conclusion Our meta-analysis indicated that TT genotype in the ERCC2 rs1799793 and ERCC5 rs2296147 might prolong the survival time of patients with osteosarcoma, suggesting that the rs1799793 and rs2296147 polymorphisms can be used as predictors for prognosis of osteosarcoma patients treated with chemotherapy.

OBJECTIVES To model the cost-effectiveness of a biomarker-based approach to select patients for neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS We obtained data from the most recent clinical studies on patients with locally advanced MIBC treated by RC, including stage distributions, overall survival (OS) estimates, associated costs, and utilisation/response to NAC. Additionally, we estimated the putative efficacy of three biomarkers to select patients for NAC: DNA-repair gene panel [ataxia telangiectasia mutated (ATM), retinoblastoma 1 (RB1), and Fanconi anaemia complementation group C (FANCC)], excision repair cross-complementation group 2 (ERCC2), and ribonucleic acid (RNA) subtypes. A decision analysis model was developed to evaluate the cost-effectiveness of biomarker-based approaches to select patients with MIBC for NAC. Comparison of cost-effectiveness included RC alone, unselected NAC plus RC, and NAC based on the three aforementioned biomarkers. RESULTS The DNA-repair gene panel-based approach to NAC was the most cost-effective strategy (mean OS of 3.14 years, $31 482/life year). Under this approach, 38% would undergo NAC, about twice the number of patients who are currently receiving NAC for MIBC. Such an approach would improve mean OS by 5.2, 1.6, and 4.4 months compared to RC alone, a hypothetical scenario where all patients received NAC, and compared to current estimates of NAC utilisation, respectively. CONCLUSIONS A biomarker-based strategy to identify patients with MIBC who should undergo NAC was more cost-effective than unselected use of NAC or RC alone. As further data becomes available, such a model may serve as a basis for incorporating biomarkers into clinical decision making.

Background DNA repair genes are crucial for maintaining genomic stability by preventing mutagenesis and carcinogenesis. The present retrospective cohort study aimed at investigating whether MLH1, APEX1, MUTYH, OGG1, NUDT1, XRCC5, XPA, and ERCC2 single nucleotide polymorphisms (SNPs) are associated with colorectal cancer (CRC) in Chinese population with Lynch syndrome. Methods From Amsterdam criteria family registry, we identified 270 patients with Lynch syndrome. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between DNA repair SNPs and CRC were calculated using a weighted Cox proportional hazard regression model. Results Heterozygous variants of rs1799832 in NUDT1 (HR = 2.97, 95% CI = 1.51-5.83) and rs13181 in ERCC2 (HR = 2.69, 95% CI = 1.10-6.55) were significantly associated with an increased risk of CRC compared with wild-type homozygous CC and TT genotypes, respectively. However, the variant CG+GG genotype of MUTYH rs3219489 was associated with a decreased risk of CRC (HR = 0.49, 95% CI = 0.26-0.91) compared with the homozygous CC wild-type counterparts. Conclusion Our findings revealed that polymorphisms of DNA repair genes that include NUDT1, ERCC2, and MUTYH are associated with CRC in patients with Lynch syndrome in Chinese population. Further studies with large sample size are needed to confirm our findings.

Jing He,1,* Zhen-Jian Zhuo,2,* Anqi Zhang,3,* Jinhong Zhu,4 Rui-Xi Hua,5 Wen-Qiong Xue,1 Shao-Dan Zhang,1 Jiang-Bo Zhang,1 Xi-Zhao Li,1 Wei-Hua Jia1 1State Key Laboratory of Oncology in South China, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; 2Faculty of Medicine, School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China; 3Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; 4Molecular Epidemiology Laboratory, Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China; 5Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China *These authors contributed equally to this work Background: Potentially functional polymorphisms can modulate protein activities and host’s DNA repair capacity, thereby influencing cancer susceptibility. The association of the polymorphisms in the nucleotide excision repair core pathway genes and gastric cancer susceptibility remains largely unknown. Methods: Here, we systematically analyzed the associations between nine polymorphisms in four key genes (XPA, ERCC1, ERCC2, and ERCC4) in the nucleotide excision repair pathway and gastric cancer risk in a Chinese population including 1142 patients and 1173 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the risk associations. Results: We observed that ERCC1 rs2298881 CA variant genotype was associated with an increased gastric cancer risk (CA vs. CC: adjusted OR [AOR]=1.33, 95% CI=1.09–1.62; dominant model: AOR=1.32, 95% CI=1.10–1.60). However, ERCC1 rs3212986 AA variant genotype was identified as a protective factor for gastric cancer (AA vs. CC: AOR=0.73, 95% CI=0.54–0.98; recessive model: AOR=0.72, 95% CI=0.54–0.96). Genotype-based mRNA expression analysis further indicated that the rs2298881 A allele was associated with decreased ERCC1 mRNA expression. Conclusion: In all, these results indicated that the ERCC1 polymorphisms may affect the risk of gastric cancer in the Chinese Han population. Keywords: gastric cancer, DNA repair, NER, polymorphism, susceptibility

Background Genetic determinants of breast cancer (BC) remained largely unknown in the majority of Moroccan patients. The purpose of this study was to explore the association of ERCC2 and MTHFR polymorphisms with genetic susceptibility to breast cancer in Moroccan population. Methods We genotyped ERCC2 polymorphisms (rs1799793 (G934A) and rs13181 (A2251C)) and MTHFR polymorphisms (rs1801133 (C677T) and rs1801131 (A1298C)) using TaqMan SNP Genotyping Assays. Genotypes were compared in 151 BC cases and 156 population-matched controls. Allelic, genotypic and haplotype associations with the risk and clinicopathological features of BC were assessed using logistic regression analyses. Results ERCC2-rs1799793-AA genotype was associated with high risk of BC compared to wild type genotype (recessive model: OR: 2.90, 95% CI: 1.34–6.26, p = 0.0069) even after Bonferroni correction (p

Background and Objective: Excision repair cross complementing (ERCC) group genes play important roles in the nucleotide excision repair (NER) way, which can effectively remove bulky lesions and reduce UV-caused DNA damage by environmental chemicals. Polymorphisms in ERCCs were thought to be related to prostate cancer (PCa) risk. However, it has been unclear whether this relationship is consistent. This study aimed to obtain the overall profile regarding the associations between ERCCs polymorphisms and PCa risk. Materials and Methods: We identified relevant studies by a systematic search of PubMed, Medline, Embase, Google Scholar databases, Web of Science and Wanfang databases up to April 8, 2018. Odds ratios (ORs) with 95% confidential intervals (95%CIs) were conducted to evaluate the associations. All the statistical analyses were conducted basing on STATA 12.0 software. Results: Finally, a total of 29 previous studies published in 17 publications were included for four polymorphisms in two DNA repair genes (ERCC2-rs1799793, ERCC2-rs238406, ERCC2-rs13181 and ERCC5-rs17655). Overall, we observed no significant connection between these four polymorphisms and PCa risk. However, after stratifying the studies by ethnicity, ERCC2-rs1799793 polymorphism was associated with an increased risk of PCa in Asian patients and the relationship was subsequently validated with the allelic model, the homozygous model and the recessive model when extracting the data of Asian patients for specific analyses (B vs. A: OR = 1.537, 95%CI: 1.240-1.906, PA 0.050). Conclusion: To sum up, our work demonstrated that ERCC2-rs1799793 polymorphism is positively associated with PCa risk in Asian population. Further larger-scale studies with subjects of the same ethnicity and biological characteristics are required to verify these findings.

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.

Objectives The inconsistent findings from genetic association studies may be related to the heterogeneity in different molecular subtypes of lung cancer. This study evaluated the predisposing single-nucleotide polymorphisms (SNPs) in epidermal growth factor receptor (EGFR) mutant and EGFR wild-type lung adenocarcinoma separately among never-smokers. Materials and methods This was a two-stage case-control study. Never-smokers with pathologically confirmed lung adenocarcinoma and healthy controls were recruited in Hong Kong and Macau. Genomic DNA was extracted and genotyped by MassARRAY. In the discovery stage, 51 SNPs were investigated at the SNP, gene and pathway level among 103 EGFR mutant and 78 EGFR wild-type lung adenocarcinoma cases compared with matched controls. In the validation stage, SNPs that were identified with significant lung cancer risk were replicated in a separate cohort of 84 lung adenocarcinoma cases and compared with 103 Chinese Han, Beijing and 105 Chinese Han, Southern public controls from the 1000 genome database. Results and conclusion The genetic association of IL-6 rs2069840 with EGFR mutant lung adenocarcinoma was ascertained. In the discovery stage, haplotype GGG in three SNPs (rs2069840, rs2069852, rs2066992) of IL-6, synergetic effects of IL-6 rs2069840 and environmental tobacco smoke in the workplace were found to be related to EGFR mutant lung adenocarcinoma. ERCC2 rs238406 showed a marginally significant association with EGFR mutant lung adenocarcinoma in the validation stage (P = 0.096). ERCC2 rs50871 and ATM rs611646 showed significant association with EGFR wild-type lung adenocarcinoma in the discovery stage. In conclusion, IL-6 rs2069840 conferred susceptibility to EGFR mutant lung adenocarcinoma in a Hong Kong and Macau never-smoking Chinese population.

Biomarker-based chemotherapy with increased efficacy and prolonged disease-free survival are urgently needed in pancreatic cancer (PDAC). A 15-20% subset of PDAC tumors carry mutations in DNA repair pathway (BRCA1/BRCA2/PALB2/RAD51/ATM/FANCD2). Additionally, mutations in nucleotide excision repair (NER) genes (ERCC2/3/4/5/6) have been reported in ~5% of PDAC. LP184 is a novel synthetic small molecule acylfulvene analog. Using precise synthetic chemistry, we determined that only a negative enantiomer of LP184 is converted to an active alkylating agent in the strict dependency on oxidoreductase, prostaglandin reductase 1 (PTGR1). By computational analyses, we demonstrate a strong positive correlation of LP184 sensitivity with PTGR1 transcript levels (r=0.89, p Citation Format: Diana Restifo, Aditya Kulkarni, Caleb Schimke, Joseph McDermott, Umesh Kathad, Kishor Bhatia, Panna Sharma, Igor Astsaturov. LP184, a novel alkylating agent, is highly effective in pancreatic cancers with DNA damage repair defects [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-036.

DNA repair genes have potential clinical value in predicting cancer prognosis and treatment outcomes. Nucleotide excision repair (NER) proteins like ERCC2 play a critical role in maintaining genome integrity by recognizing and unwinding DNA at sites of damage1.Aberrant expression of ERCC2 alters NER capacity, influencing treatment outcomes2. The current investigation examined the expression of ERCC2 following epigenetic combination treatment in colorectal cancer (CRC) cells and preclinical models. Attention was drawn to ERCC2 based on three observations. First, from online databases, when ERCC2 was overexpressed in colon tumors the corresponding CRC patients had reduced overall survival3. Second, ERCC2 was the most highly downregulated gene when dietary histone deacetylase 3 (HDAC3) inhibitor sulforaphane (SFN) was combined withJQ1, an inhibitor of the bromodomain and extra terminal domain family, in human colon cancer cells and in colon polyps from the polyposis in rat colon (Pirc) model4. Third, as reported here for the first time, RNA-seq analyses of Pirc colon polyps from rats treated withJQ1 and the SFN analog 6-SFN5 identified Ercc2 as the most highly downregulated gene. RNA-seq data were corroborated by RT-qPCR and immunoblotting experiments. There is much interest in combination approaches that target epigenetic ‘readers, writers, and erasers' that are deregulated in cancer and other pathologies. The current work identified promising second-generation inhibitors with enhanced synergy and antitumor efficacy, especially in metastatic cells cultured in three-dimensions. Drug combinations decreased HDAC3, BRD4 and ERCC2 expression, while DNA damage and apoptosis markers were increased both in spheroids and in a mouse xenograft model. This investigation has potential clinical relevance for the identification of robust biomarkers that predict enhanced antitumor outcomes in CRC patients.1. Gillet LC, Schärer OD. Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem Rev 2006;106:253-76.2. Shuck SC, Short EA, Turchi JJ. Eukaryotic nucleotide excision repair: from understanding mechanisms to influencing biology. Cell Res 2008;18:64-72.3. Liu J et al., The Differential Expression of Core Genes in Nucleotide Excision Repair Pathway Indicates Colorectal Carcinogenesis and Prognosis. Biomed Res Int 2018;2018:9651320.4. Rajendran P et al., Acetylation of CCAR2 establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition. Cancer Res 2019;79:918-27.5. Rajendran Pet al., HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cell treated with sulforaphane and related dietary isothiocyanates. Epigenetics 2013;8:612-23. Citation Format: Sabeeta Kapoor, Trace Gustafson, Mutian Zhang, Ying-Shiuan Chen, Jia Li, Nhung Nguyen, Jorge Enrique Perez, Wan Mohaiza Dashwood, Praveen Rajendran, Roderick Dashwood. Combined deacetylase and bromodomain inhibition downregulates ERCC2 and suppresses growth of metastatic colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2106.

A growing number of studies investigating the association between Single Nucleotide Polymorphisms (SNPs) and lung cancer risk have been published since over a decade ago. An updated integrative assessment on the credibility and strength of the associations is required. We searched PubMed, Medline, and Web of Science on or before August 29th, 2016. A total of 198 articles were deemed eligible for inclusion, which addressed the associations between 108 variants and lung cancer. Among the 108 variants, 63 were reported to be significantly associated with lung cancer while the remaining 45 were reported non-significant. Further evaluation integrating the Venice Criteria and false-positive report probability (FPRP) was performed to determine the strength of cumulative epidemiological evidence for the 63 significant associations. As a result, 15 SNPs on or near 12 genes and one miRNA with strong evidence of association with lung cancer risk were identified, including TERT (rs2736098), CHRNA3 (rs1051730), AGPHD1 (rs8034191), CLPTM1L (rs401681 and rs402710), BAT3 (rs3117582), TRNAA (rs4324798), ERCC2 (Lys751Gln), miR-146a2 (rs2910164), CYP1B1 (Arg48Gly), GSTM1 (null/present), SOD2 (C47T), IL-10 (-592C/A and -819C/T), and TP53 (intron 6). 19 SNPs were given moderate rating and 17 SNPs were rated as having weak evidence. In addition, all of the 29 SNPs identified in 12 genome-wide association studies (GWAS) were proved to be noteworthy based on FPRP value. This review summarizes and evaluates the cumulative evidence of genetic polymorphisms and lung cancer risk, which can serve as a general and useful reference for further genetic studies.

To investigate correlations between excision repair cross-complementation group 1 (ERCC1) and 2 (ERCC2) polymorphisms and osteosarcoma prognosis, we conducted a meta-analysis of studies published through October 2016. Studies were identified in the PubMed, ScienceDirect, Springer, and Web of Science databases using preferred reporting items for systematic reviews and meta-analyses (PRISMA). Odds ratios (ORs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS), tumor response (TR), and event-free survival (EFS) were estimated. Our meta-analysis included eleven studies in which four SNPs (ERCC1 rs11615 and rs3212986, ERCC2 rs13181 and rs1799793) reportedly associated with osteosarcoma prognosis were investigated. Each of these studies scored > 6 on the Newcastle-Ottawa Scale (NOS). We found that only one SNP, ERCC1 rs11615, correlated with improved OS and TR. The HR of T vs. C for OS was 1.455 (T/C, 95% CI = 1.151–1.839, P = 0.002, I2 = 37.80%). The OR of T vs. C for good TR was 0.554 (T/C, 95% CI = 0.437–0.702, P < 0.001, I2 = 0%). Few significant outcome was observed in subgroup analyses stratified based on study characteristics with adjustments for potential confounders. Our results suggest that ERCC1 rs11615 CC is associated with a better clinical outcome. This suggests rs11615 may be a useful genetic marker for predicting osteosarcoma prognosis.

Genetic variants in the excision repair cross-complimentary group 2 (ERCC2) gene may affect individual susceptibility to cancer by modulating the capability of DNA damage repair. However, the current studies concerning the association of ERCC2 rs13181 polymorphism with ovarian cancer risk provided inconsistent evidence. This study was to quantitatively summarize the evidence from the individual studies electronically retrieved by a meta-analysis. Totally, nine eligible case–control studies with 1333 cases and 2691 controls were included for the concerned association. Overall, a significant association between ERCC2 gene rs13181 polymorphism and increased risk of ovarian cancer was revealed (CC+AC vs. AA: OR 1.44, 95% CI 1.11–1.86; CC vs. AA: OR 2.12, 95% CI 1.14–3.97). Similarly, in the subgroup analyses, such association was also evident in non-Caucasian population and hospital-based studies. Noteworthily, the recombined analysis with a significant decrease in between-heterogeneity represented a significant association of the variant with increased risk of ovarian cancer after excluding the individual study not in agreement with HWE. The present study suggests that the ERCC2 gene rs13181 polymorphism might be associated with increased risk of ovarian cancer.