Single Nucleotide Polymorphisms In DNA Repair Genes Research Articles

Gene-Environment Analyses in a UK Biobank Skin Cancer Cohort Identifies Important SNPs in DNA Repair Genes That May Help Prognosticate Disease Risk.

Despite well-established relationships between sun exposure and skin cancer pathogenesis/progression, specific gene-environment interactions in at-risk individuals remain poorly-understood. We leveraged a UK Biobank cohort of basal cell carcinoma (BCC, n = 17,221), cutaneous squamous cell carcinoma (cSCC, n = 2,331), melanoma in situ (M-is, n = 1,158), invasive melanoma (M-inv, n = 3,798), and healthy controls (n = 448,164) to quantify the synergistic involvement of genetic and environmental factors influencing disease risk. We surveyed 8,798 SNPs from 190 DNA repair genes, and 11 demographic/behavioral risk factors. Clinical analysis identified darker skin (RR = 0.01-0.65) and hair (RR = 0.27-0.63) colors as protective factors. Eleven SNPs were significantly associated with BCC, three of which were also associated with M-inv. Gene-environment analysis yielded 201 SNP-environment interactions across 90 genes (FDR-adjusted q<0.05). SNPs from the FANCA gene showed interactions with at least one clinical factor in all cancer groups, of which three (rs9926296, rs3743860, rs2376883) showed interaction with nearly every factor in BCC and M-inv. We identified novel risk factors for keratinocyte carcinomas and melanoma, highlighted the prognostic value of several FANCA alleles among individuals with a history of sunlamp use and childhood sunburns, and demonstrated the importance of combining genetic and clinical data in disease risk stratification. This study revealed genome-wide associations with important implications for understanding skin cancer risk in the context of the rapidly-evolving field of precision medicine. Major individual factors (including sex, hair and skin color, and sun protection use) were significant mediators for all skin cancers, interacting with >200 SNPs across four skin cancer types.

Анализ связи полиморфного локуса rs1052133 гена OGG1 с риском развития злокачественных новообразований у людей, подвергшихся радиационному воздействию

Genetic predisposition without doubt is one of the risk factors of cancer initiation. It is known that single nucleotide polymorphisms (SNP) of genes that maintain the genome stability, including SNP of DNA repair, may contribute to the initiation of carcinogenesis. Single-nucleotide polymorphisms of genes that support genome stability, including SNP of DNA repair genes, can contribute to cancer initiation. Polymorphism of the excision repair gene OGG1 causes interest of leading scientific groups from various countries. It is assumed that there is relationship between the rs1052133 polymorphism in the gene and predisposition to cancer initiation. The objective of this study was to establish association between rs1052133 polymorphism of base excision repair gene OGG1 and the risk of cancer initiation in people chronically exposed to ionizing radiation. Residents (888 people) of the Techa riverside settlements, chronically exposed to low or medium radiation from the Techa River and the East-Urals Radioactive Trace were included in the study. The study allowed researchers to establish that exposed to chronic radiation people, carriers of the rs1052133*G allele have increased risk of malignant neoplasms initiation: OR=1.38; 95% CI [1.05-1.83], p=0.023. The multifactorial synergistic interactions between the dose to the red bone marrow and the rs1052133 polymorphism of the OGG1 gene was found: Testing Balanced Accuracy (TBA)=0.56; Cross Validation Consistency (CVC)=10/10; p=0.01). The study found that the rs1052133 polymorphism may be considered as genetical marker of risk of cancer initiation in people, chronically exposed to radiation with doses ranged from 0.74 to 3507.07 mGy (average 523.10+/-33.89 mGy). It was found that the presence of the rs1052133*G in combination with radiation exposure can modify the risk of solid cancers initiation, as it is indicated by the synergistic relationship between the SNP and the radiation dose.

Thyroid Cancer: The Quest for Genetic Susceptibility Involving DNA Repair Genes

The incidence of thyroid cancer (TC), particularly well-differentiated forms (DTC), has been rising and remains the highest among endocrine malignancies. Although ionizing radiation (IR) is well established on DTC aetiology, other environmental and genetic factors may also be involved. DNA repair single nucleotide polymorphisms (SNPs) could be among the former, helping in explaining the high incidence. To further clarify the role of DNA repair SNPs in DTC susceptibility, we analyzed 36 SNPs in 27 DNA repair genes in a population of 106 DTCs and corresponding controls with the aim of interpreting joint data from previously studied isolated SNPs in DNA repair genes. Significant associations with DTC susceptibility were observed for XRCC3 rs861539, XPC rs2228001, CCNH rs2230641, MSH6 rs1042821 and ERCC5 rs2227869 and for a haplotype block on chromosome 5q. From 595 SNP-SNP combinations tested and 114 showing relevance, 15 significant SNP combinations (p < 0.01) were detected on paired SNP analysis, most of which involving CCNH rs2230641 and mismatch repair variants. Overall, a gene-dosage effect between the number of risk genotypes and DTC predisposition was observed. In spite of the volume of data presented, new studies are sought to provide an interpretability of the role of SNPs in DNA repair genes and their combinations in DTC susceptibility.

Data on Single Nucleotide Polymorphism of DNA Repair Genes and Breast Cancer Risk from Poland.

Single nucleotide polymorphisms (SNPs) may modify the risk of cancer. They may be then regarded as potential markers of carcinogenesis. The aim of this study was to analyze the frequency of genotypes and alleles of SNPs in DNA repair genes and to investigate the influence this genetic variation exerts on breast cancer in Polish females. The test group comprised 600 females with breast cancer and 600 healthy controls. Genomic DNA was isolated and the SNPs in DNA repair genes were determined by High-Resolution Melter (HRM) technique. Following polymorphisms were analysed: Arg399Gln (rs25487) of the XRCC1, Gly322Asp (rs4987188) of the hMSH2, Lys751Gln (rs13181) of the XPD, Arg188His (rs3218536) of the XRCC2, P871L (rs799917) of the BRCA1 and N372H (rs144848) of the BRCA2 gene. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele. Statistically significant correlations were identified between 4 single nucleotide polymorphisms and the breast cancer risk: rs25487 rs4987188 rs13181 and rs799917. The alleles XRCC1-Gln (OR 5.11; 95% CI 5.68-11.64, p < .0001), hMSH2-Asp (OR 4.66; 95% CI 3.90-5.56, p < .0001), XPD-Gln (OR 2.65; 95% CI 2.24-3.14, p < .0001) and BRCA1-L (OR 1.45; 95% CI 1.24-1.71, p < .0001) genes were strongly correlated with this malignancy. No correlation was found between the studied SNPs and tumor grading nor the lymph node status. Further research on larger groups is warranted to determine the influence of above-mentioned genetic variants on breast cancer risk.

Single nucleotide polymorphisms in DNA repair genes and putative cancer risk.

Single nucleotide polymorphisms (SNPs) are the most frequent type of genetic alterations between individuals. An SNP located within the coding sequence of a gene may lead to an amino acid substitution and in turn might alter protein function. Such a change in protein sequence could be functionally relevant and therefore might be associated with susceptibility to human diseases, such as cancer. DNA repair mechanisms are known to play an important role in cancer development, as shown in various human cancer syndromes, which arise due to mutations in DNA repair genes. This leads to the question whether subtle genetic changes such as SNPs in DNA repair genes may contribute to cancer susceptibility. In numerous epidemiological studies, efforts have been made to associate specific SNPs in DNA repair genes with altered DNA repair and cancer. The present review describes some of the common and most extensively studied SNPs in DNA repair genes and discusses whether they are functionally relevant and subsequently increase the likelihood that cancer will develop.

Polymorphisms in DNA Repair Gene XRCC1 (Arg194Trp) and (Arg399Gln) and their Role in the susceptibility of Bacterial Meningitis

Meningitis is a contagious infectious disease with high rates of mortality. Most pathogenic microbes in humans have the ability to cause bacterial meningitis. However, the most common pathogens are Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b (Hib). It was found that the susceptibility to this infectious disease may be related to genetic characteristics of the host, such as the occurrence of single nucleotide polymorphisms (SNPs). In our previous work, association of SNPs in DNA repair genes with bacterial meningitis (BM) was demonstrated. In this study we evaluated two non-synonymous SNPs of the repair gene XRCC1 Arg194Trp (rs 1799782) and Arg399Gln (rs 25487) in patients with BM and health volunteers. The patient genotypes were investigated by PCR-RFLP. DNA damages were quantified using the genomic DNA with formamidopyrimidine DNA-glycosylase (FPG). Cytokines and chemokines were quantified from cerebrospinal fluid samples from BM patients. Concerning the SNP XRCC1 Arg194Trp, none association was found relation to BM. However, a higher frequency of heterozygous genotype for XRCC1 Arg399Gln was observed in the control group compared to the BM group (P=0.043; OR=0.426). DNA damage and cytokine/chemokines levels were not positively correlated with polymorphic genotypes. In conclusion, there is an indication that the SNP XRCC1 Arg399Gln could have a possible protective effect against BM.

Frequency distribution of DNA repair genes ERCC1 and ERCC2 polymorphisms in South Indian healthy population

DNA repair genes are crucial in maintaining the integrity of the whole genome. Single nucleotide polymorphisms (SNPs) in DNA repair genes have been attributed to the development of various cancers. SNPs of DNA repair genes (ERCC1 and ERCC2) have been implicated in the causation of various cancers as well as inter-individual variability in the therapeutic outcomes of platinum based therapy. Thus establishing the frequency of these functional SNPs in the healthy population is of significance. The present study was aimed to establish the allele and genotype frequencies of ERCC1 (19007C>T, rs11615; 8092C>A, rs3212986) and ERCC2 (Asp312Asn, rs1799793) genes in South Indian healthy population and to compare the data from HapMap populations. The study population consisted of 128 healthy South Indian unrelated individuals of either sex aged between 18 and 60 years. Standard phenol–chloroform method was used to extract DNA from peripheral leukocytes. The genotype of DNA repair gene polymorphisms was determined by quantitative real-time polymerase chain reaction using TaqMan genotyping assay. The observed frequency of the studied polymorphisms followed Hardy–Weinberg equilibrium (p>0.05). The frequencies of the minor alleles of the SNPs rs11615 (T), rs3212986 (A) and rs1799793 (A) were 43.8%, 29.3% and 35.6%, respectively. Gender-based analysis showed no significant difference in the frequency pattern. The observed allele and genotype frequencies showed significant ethnic difference between South Indians and other HapMap populations. This is the first study to provide the normative frequency data of allele and genotype distribution of three SNPs of ERCC1 and ERCC2 in South Indian healthy population. It might be useful in future genotype–phenotype association studies, especially for predicting the efficacy and adverse events of platinum based drugs.

Polymorphisms in base excision repair genes: Breast cancer risk and individual radiosensitivity.

Breast cancer (BC) is the most common cancer among women worldwide. The aetiology and carcinogenesis of BC are not clearly defined, although genetic, hormonal, lifestyle and environmental risk factors have been established. The most common treatment for BC includes breast-conserving surgery followed by a standard radiotherapy (RT) regimen. However, radiation hypersensitivity and the occurrence of RT-induced toxicity in normal tissue may affect patients' treatment. The role of DNA repair in cancer has been extensively investigated, and an impaired DNA damage response may increase the risk of BC and individual radiosensitivity. Single nucleotide polymorphisms (SNPs) in DNA repair genes may alter protein function and modulate DNA repair efficiency, influencing the development of various cancers, including BC. SNPs in DNA repair genes have also been studied as potential predictive factors for the risk of RT-induced side effects. Here, we review the literature on the association between SNPs in base excision repair (BER) genes and BC risk. We focused on X-ray repair cross complementing group 1 (XRCC1), which plays a key role in BER, and on 8-oxoguanine DNA glycosylase 1, apurinic/apyrimidinic endonuclease 1 and poly (ADP-ribose) polymerase-1, which encode three important BER enzymes that interact with XRCC1. Although no association between SNPs and radiation toxicity has been validated thus far, we also report published studies on XRCC1 SNPs and variants in other BER genes and RT-induced side effects in BC patients, emphasising that large well-designed studies are needed to determine the genetic components of individual radiosensitivity.

Polymorphisms in DNA repair and apoptosis-related genes and clinical outcomes of patients with non-small cell lung cancer treated with first-line paclitaxel-cisplatin chemotherapy

This study was conducted to analyze a comprehensive panel of single nucleotide polymorphisms (SNPs) in genes in DNA repair and apoptosis pathways and determine the relationship between polymorphisms and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with first-line paclitaxel-cisplatin chemotherapy. Three hundred eighty two patients with NSCLC were enrolled. Seventy-four SNPs in 48 genes (42 SNPs in 27 DNA repair pathway genes and 32 SNPs in 21 apoptotic pathway genes) were genotyped and their associations with chemotherapy response and overall survival (OS) were analyzed. Among SNPs in DNA repair genes, BRCA1 rs799917 was significantly associated with both chemotherapy response and OS. XRCC1 rs25487 exhibited a significant association with chemotherapy response and ERCC2 rs1052555 with OS. Four SNPs in apoptotic genes (TNFRSF1B rs1061624, BCL2 rs2279115, BIRC5 rs9904341, and CASP8 rs3769818) were significantly associated with OS, but not with response to chemotherapy. When the six SNPs which were associated with OS in individual analysis were combined, OS decreased as the number of bad genotypes increased (Ptrend=2×10−6). Patients with 3, and 4–6 bad genotypes had significantly worse OS compared with those carrying 0–2 bad genotypes (adjusted hazard ratio [aHR]=1.54, 95% CI=1.14–2.08, P=0.005; aHR=2.10, 95% CI=1.55–2.85, P=2×10−6, respectively). In conclusion, these findings suggest that the six SNPs identified, particularly their combined genotypes, could be used as biomarkers predicting chemotherapy response and survival of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.

Role of XRCC3, XRCC1 and XPD single-nucleotide polymorphisms in survival outcomes following adjuvant chemotherapy in early stage breast cancer patients

Anthracyclines have various mechanisms of action that in the end lead to DNA double-strand breaks. Single-nucleotide polymorphisms (SNPs) in DNA repair genes may alter the protein function, affecting DNA repair proficiency and, therefore, the efficiency of DNA damaging chemotherapy. We have analysed whether SNPs in DNA repair genes (XRCC1, XRCC3 and XPD) could be useful to predict the response to anthracyclines in patients with early-stage breast cancer (EBC). Peripheral blood samples from 150 patients with EBC were used for genotyping XRCC3Thr241Met, XRCC1Arg399Gln and XPDLys751Gln. Genotypes were correlated with survival outcomes. Eighty-four patients received treatment with chemotherapy regimens containing anthracyclines. In this group, patients with XRCC1Arg399Arg had a significant improvement in 5-year Disease Free Survival (DFS) compared with those with the Arg/Gln and Gln/Gln variants (84 vs 46 %, p = 0.026). In the multivariate analysis, XRCC1Arg399Arg was reported as an independent prognostic factor for DFS (HR 0.4, CI-95 % 0.2-0.9, p = 0.035). Patients with the XRCC3 Met241Met genotype presented better 5-year OS than those carrying the Thr/Thr and Met/Thr variants (100 vs 70 %, p = 0.030). A multivariate analysis for OS confirmed the independent prognostic value of XRCC3 Met241Met (HR 0.15, CI-95 % 0.02-0.90, p = 0.048). These differences were not significant when patients receiving other chemotherapy treatments, different from anthracyclines, were also considered (n = 150). XPDLys751Lys was associated with older age at diagnosis than the Lys/Gln and Gln/Gln genotypes (65 vs 58 years, p < 0.0001). XRCC3Thr241Met and XRCC1Arg399Gln may be predictive of survival outcome in EBC patients treated with anthracycline-based chemotherapy regimens.

Molecular epidemiology of DNA repair gene polymorphisms and head and neck cancer

Although tobacco and alcohol consumption are two common risk factors of head and neck cancer (HNC), other specific etiologic causes, such as viral infection and genetic susceptibility factors, remain to be understood. Human DNA is often damaged by numerous endogenous and exogenous mutagens or carcinogens, and genetic variants in interaction with environmental exposure to these agents may explain interindividual differences in HNC risk. Single nucleotide polymorphisms (SNPs) in genes involved in the DNA damage-repair response are reported to be risk factors for various cancer types, including HNC. Here, we reviewed epidemiological studies that have assessed the associations between HNC risk and SNPs in DNA repair genes involved in base-excision repair, nucleotide-excision repair, mismatch repair, double-strand break repair and direct reversion repair pathways. We found, however, that only a few SNPs in DNA repair genes were found to be associated with significantly increased or decreased risk of HNC, and, in most cases, the effects were moderate, depending upon locus-locus interactions among the risk SNPs in the pathways. We believe that, in the presence of exposure, additional pathway-based analyses of DNA repair genes derived from genome-wide association studies (GWASs) in HNC are needed.

Abstract 2634: Polymorphisms in DNA repair genes and risk of multiple myeloma

Abstract Background and Objective: DNA repair is an essential process for development and differentiation of all cells, including plasma cells. Associations between single nucleotide polymorphisms (SNPs) in DNA repair genes and multiple myeloma risk have been reported but generally not replicated. In a pilot study, we observed suggestive evidence of an association between multiple myeloma risk and five nonsynonymous SNPs in DNA repair genes (rs25489 in XRCC1, rs1801516 in ATM, rs2227999 in XPC, rs2228528 in CSB and rs2228615 in ICAM5). The objective of this study was to examine the effect of these five SNPs on multiple myeloma risk in a large multi-center analysis. Methods: We conducted a pooled analysis in a multi-ethnic sample of 489 multiple myeloma cases and 939 controls. Studies contributing samples included two population-based case-control studies conducted in Los Angeles and Seattle/Detroit that used the Surveillance, Epidemiology and End Results (SEER) cancer registries to identify cases, and three nested case-control studies using subjects from the Multiethnic Cohort (MEC), the Health Professionals Follow Up Study (HPFS), and the Nurses’ Health Study (NHS). The SNPs coded for an amino acid substitution, and were assumed to have the same effect across ethnic groups, and thus subjects from all racial/ethnic groups were included in the analysis. Assuming a log-additive inheritance model, odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated for allele-specific risk comparing cases to controls using unconditional logistic regression, adjusting for age, race/ethnicity, sex, and study site. Results: We observed a 40% decreased risk per variant T allele in the XRCC1 SNP rs25489 (OR=0.60, 95% CI=0.40, 0.91, p-value=0.02). The minor allele frequency in cases and controls was 3.4% and 5.6%, respectively. Non-significant OR's &amp;lt; 1.0 were observed when whites (OR=0.67, 95% CI=0.38, 1.17) and African Americans (OR=0.33, 95% CI= 0.09, 1.20) were considered separately. The SNPs in other DNA repair genes, ATM (rs1801516), XPC (rs2227999), CSB (rs2228528) and ICAM5 (rs2228615), showed no association with multiple myeloma risk. Conclusion: We observed an association between multiple myeloma and XRCC1, a gene that encodes a protein involved in the repair of single-stranded DNA breaks caused by ionizing radiation and alkylating agents. The variant allele of rs25489 results in a missense mutation substituting an amino acid (Arg &amp;gt; His). Several studies have shown diminished DNA repair capacity associated with the variant allele of this SNP, an effect which may be relevant to multiple myeloma etiology. Replication in additional studies is needed to validate this finding. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2634. doi:1538-7445.AM2012-2634

Hodgkin lymphoma risk: role of genetic polymorphisms and gene-gene interactions in DNA repair pathways.

DNA repair variants may play a potentially important role in an individual's susceptibility to developing cancer. Numerous studies have reported the association between genetic single nucleotide polymorphisms (SNPs) in DNA repair genes and different types of hematologic cancers. However, to date, the effects of such SNPs on modulating Hodgkin lymphoma (HL) risk have not yet been investigated. We hypothesized that gene-gene interaction between candidate genes in direct reversal, nucleotide excision repair (NER), base excision repair (BER) and double strand break (DSB) pathways may contribute to susceptibility to HL. To test this hypothesis, we conducted a study on 200 HL cases and 220 controls to assess associations between HL risk and 21 functional SNPs in DNA repair genes. We evaluated potential gene-gene interactions and the association of multiple polymorphisms in a chromosome region using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction and classification and regression tree approaches. We observed that, in combination, allelic variants in the XPC Ala499Val, NBN Glu185Gln, XRCC3 Thr241Me, XRCC1 Arg194Trp, and XRCC1 399Gln polymorphisms modify the risk for developing HL. Moreover, the cumulative genetic risk score revealed a significant trend where the risk for developing HL increases as the number of adverse alleles in BER and DSB genes increase. These findings suggest that DNA repair variants in BER and DSB pathways may play an important role in the development of HL.

Single-nucleotide polymorphisms in DNA-repair genes and cutaneous melanoma

Single-nucleotide polymorphisms in different DNA-repair genes are reported to modulate risk of various cancers including melanoma. We genotyped DNA from 1186 melanoma patients and 1280 healthy controls for 13 different polymorphisms in eight DNA-repair genes. Data analyses showed that none of the polymorphisms except T241M XRCC3 was associated with an increased risk for cutaneous melanoma. Carriers of the variant alleles were associated with a decreased risk (OR 0.83; 95% CI, 0.79–0.98). Three additional polymorphisms together with T241M XRCC3 that tagged the entire gene region and the neighbouring genes KLC1, ZFYVE21 and PPP1R13B were not associated with the disease risk; neither were the inferred haplotypes. Imputation showed association of comparable magnitude with 11 non-genotyped neighbouring polymorphisms. Finally, the combination of results for all polymorphisms genotyped in the present study with published data suggests that none of the investigated polymorphisms was associated with melanoma susceptibility. We conclude that 13 non-synonymous polymorphisms in eight DNA-repair genes that are frequently investigated with respect to modulation of cancer risk in populations are not associated with susceptibility to cutaneous melanoma.

849 Cetuximab penetration and EGFR expression in tumour spheroids: prerequisite for testing a new radiotherapeutic approach

Single nucleotide polymorphisms (SNPs) in DNA repair genes may impact on DNA damage, and cancer risk. To elucidate the role of SNPs in DNA repair genes in prostate cancer (PC) we conducted a case-control study comprising of 118 Caucasian men affected with late onset PC and 132 age-matched healthy controls from South Australia.We examined the association between PC risk with nonsynonymous SNPs (nsSNPs) in 5 genes involved in 3 DNA-repair pathways: (1) base excision repair (BER): hOGG1 C1245G (Ser326Cys) and XRCC1 G28152A (Arg399Gln); (2) nucleotide excision repair (NER): XPD G23591A (Asp312Asn); (3) homologous recombination repair: RAD51 G135C (in 5′ untranslated region) and XRCC3 C18067T (Thr241Met).Prostate cancer risk was significantly increased only for carriers of the G allele of the C1245G polymorphism in the hOGG1 gene (OR = 2.28; 95% CI = 1.36–3.83; P = 0.002).Our results suggest that this common nsSNP in a gene involved in repair of oxidative damage to DNA may contribute to PC susceptibility in South Australian men.

The Host Genetic Background of DNA Repair Mechanisms Represents An Independent Predictor of Progression and Survival in Diffuse Large B-Cell Lymphoma Treated with R-CHOP.

Abstract 442Scant information is availabel on the impact of the host genetic background in predicting outcome of diffuse large B cell lymphoma (DLBCL). We recently documented that host single nucleotide polymorphisms (SNPs) affecting doxorubicin pharmacodynamics and alkylator detoxification may predict outcome in R-CHOP-treated DLBCL (Rossi et al, Leukemia 2009; 23:118-26). Several DNA repair mechanisms are involved in resistance to R-CHOP drugs. We verified whether SNPs of DNA repair genes may further refine prognostic stratification and toxicity prediction in DLBCL treated with R-CHOP. The study was based on 163 consecutive DLBCL treated with R-CHOP and provided with a prospectively collected dataset. At diagnosis, age >60 years was observed in 104/163 (63.8%) cases, ECOG PS >1 in 21/163 (12.9%), extranodal sites >1 in 41/163 (25.2%), Ann Arbor stage III-IV in 85/163 (52.1%), bulky disease in 46/163 (28.2%), B symptoms in 38/163 (23.3%), LDH elevation in 75/163 (46.0%), IPI >2 in 55/163 (33.7%). Median follow up was 40 months. Candidate SNPs selected for the analysis belonged to genes involved in repairing DNA damage produced by R-CHOP drugs, and included SNPs affecting the following DNA repair mechanisms: i) base excision repair (OGG1 rs1052133); ii) nucleotide excision repair (ERCC2 rs1799793, ERCC2 rs13181, ERCC6 rs3793784, ERCC6 rs2228528, ERCC6 rs2228529, XPA rs1800975, XPC rs2227999, XPC rs2228000); iii) mismatch repair (MLH1 rs1799977); iv) double strand break repair (LIG4 rs1805388, XRCC6 rs132788, XRCC6 rs55751129, BRCA1 rs799917). Genotyping was performed by SNP-minisequencing on DNA extracted from granulocytes. Clinical endpoints considered in the study were overall survival (OS), progression free survival (PFS) and toxicity. Associations of SNPs with clinical endpoints were controlled for multiple testing by FDR analysis. Among the SNPs included in the study, univariate log-rank analysis controlled for multiple comparisons by FDR testing identified MLH1 rs1799977 as a predictor of both PFS and OS in DLBCL treated with R-CHOP. MLH1 encodes a DNA mismatch repair gene involved in alkylating agents and doxorubicin resistance. DLBCL patients carrying the MLH1 rs1799977 AG/GG genotypes displayed a poorer PFS (Events/N: 23/52; 3-year PFS: 51.9%) compared to DLBCL patients carrying the MLH1 rs1799977 AA genotype (Events/N: 33/111; 3-year PFS: 72.0%) (p=.020; q=.240) (Fig. 1). Other variables predicting PFS were ECOG PS (p=.042), Ann Arbor stage (p=.035), bulky disease (p=.001), number of extranodal sites (p=.009), LDH (p=.007), and IPI (p=.002). Multivariate analysis selected MLH1 rs1799977 AG/GG (HR: 1.17; p=.034) as an independent predictor of PFS, along with IPI (HR: 1.44; p=.002) and bulky disease (HR: 2.20, p=.004). The MLH1 rs1799977 genotype was also relevant for predicting DLBCL survival, since DLBCL patients carrying the MLH1 rs1799977 AG/GG genotypes displayed a poorer OS (Events/N: 19/52; 3-year OS: 61.8%) compared to DLBCL patients carrying the MLH1 rs1799977 AA genotype (Events/N: 18/111; 3-year OS: 83.3%) (p=.001; q=.013) (Fig. 2). Other variables predicting OS were age (p=.026), ECOG PS (p=.002), bulky disease (p<.001), number of extranodal sites (p=.027), IPI (p=.020), relative dose intensity of doxorubicin (p=.017), and comorbidity score (p=.003). Multivariate analysis selected MLH1 rs1799977 AG/GG (HR: 2.84; p=.002) as an independent predictor of OS, along with IPI (HR: 1.40; p=.013) and bulky disease (HR: 3.20; p=.001). The impact of SNPs was also evaluated for toxicity in 803 R-CHOP courses. A multivariate model for toxicity was built by generalized estimating equations (GEE), which adjust for the clustering of treatment courses within a patient. After correcting for multiple comparisons and adjusting for potentially confounding variables, none of the DNA repair SNPs analysed was found to be associated with R-CHOP toxicity. Overall, MLH1 rs1799977 SNP is an independent predictor of progression and survival in DLBCL treated with R-CHOP. The biologic plausibility of this association is supported by two lines evidence: i) MLH1 rs1799977 G variant allele is known to reduce MLH1 protein expression and function; ii) loss of MLH1 DNA mismatch repair function is known to result in in vitro resistance to doxorubicin and alkylating agents. Consistently, DLBCL carriers of the MLH1 rs1799977 AG/GG genotypes displayed poor PFS and OS possibly due to altered MLH1 function. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Association Between Genetic Polymorphism in DNA Repair Genes and Acute Myeloid Leukemia.

Abstract 4131Genetic variants in DNA repair genes may affect DNA repair capacity and modulate cancer susceptibility. We analyzed genetic polymorphisms of 11 DNA repair genes: XRCC4, BRCA1, WRN, RAD51, XRCC3, ERCC1, ERCC2, XPC, OGG1, XRCC1 and MGMT to evaluate the association and risk of acute myeloid leukemia (AML). A large-scale population-based, case-control study of 1700 controls and 659 cases was conducted in Chonnam National University Hwasun Hospital, Korea.Three single-nucleotide polymorphisms(SNPs), ERCC1 IVS5 +33 CC, WRN 787 GG and XRCC1 399 GA genotypes were associated with decreased risk for AML [odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.54-0.92, p=0.01 for IVS5 +33 CC, 0.67; 0.50–0.89, p=0.006 for 3149 GG and 0.81; 0.67–0.98, p=0.031 for 1316 GA]. We found no differences in the XRCC4 S307, BRCA1 P87L, RAD51 –G135C, XRCC3 T241M, ERCC2 K751Q, XPC K939Q, OGG1 S326C and MGMT L84F genotypes.Our results suggest that these 3 SNPs in DNA repair genes may affect AML susceptibility by modulating activities to maintain the genome integrity of each individual. Disclosures:No relevant conflicts of interest to declare.

DNA repair gene polymorphisms and prostate cancer risk in South Australia—results of a pilot study

Objective Single nucleotide polymorphisms (SNPs) in DNA repair genes may impact on DNA damage, and cancer risk. To elucidate the role of SNPs in DNA repair genes in prostate cancer (PC) we conducted a case-control study comprising of 118 Caucasian men affected with late onset PC and 132 age-matched healthy controls from South Australia. Methods and materials We examined the association between PC risk with nonsynonymous SNPs (nsSNPs) in 5 genes involved in 3 DNA-repair pathways: (1) base excision repair (BER): hOGG1 C1245G (Ser326Cys) and XRCC1 G28152A (Arg399Gln); (2) nucleotide excision repair (NER): XPD G23591A (Asp312Asn); (3) homologous recombination repair: RAD51 G135C (in 5′ untranslated region) and XRCC3 C18067T (Thr241Met). Results Prostate cancer risk was significantly increased only for carriers of the G allele of the C1245G polymorphism in the hOGG1 gene (OR = 2.28; 95% CI = 1.36–3.83; P = 0.002). Conclusion Our results suggest that this common nsSNP in a gene involved in repair of oxidative damage to DNA may contribute to PC susceptibility in South Australian men.

Genetic variation in DNA repair genes and prostate cancer risk: results from a population-based study.

DNA repair pathways are crucial to prevent accumulation of DNA damage and maintain genomic stability. Alterations of this pathway have been reported in many cancers. An increase in oxidative DNA damage or decrease in DNA repair capacity with aging or due to germline genetic variation may affect prostate cancer risk. Pooled data from two population-based studies (1,457 cases and 1,351 controls) were analyzed to examine associations between 28 single-nucleotide polymorphisms (SNPs) in nine DNA repair genes (APEX1, BRCA2, ERCC2, ERCC4, MGMT, MUTYH, OGG1, XPC, and XRCC1) and prostate cancer risk. We also explored whether associations varied by smoking, by family history or clinical features of prostate cancer. There were no associations between these SNPs and overall risk of prostate cancer. Risks by genotype also did not vary by smoking or by family history of prostate cancer. Although two SNPs in BRCA2 (rs144848, rs1801406) and two SNPs in ERCC2 (rs1799793, rs13181) showed stronger associations with high Gleason score or advanced-stage tumors when comparing homozygous men carrying the minor versus major allele, results were not statistically significantly different between clinically aggressive and non-aggressive tumors. Overall, this study found no associations between prostate cancer and the SNPs in DNA repair genes. Given the complexity of this pathway and its crucial role in maintenance of genomic stability, a pathway-based analysis of all 150 genes in DNA repair pathways, as well as exploration of gene-environment interactions may be warranted.

Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines

The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearson's correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p<or=0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3241 and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p<or=0.001).