Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: XRCC3 (cancer-related)
Rudnicka K, Backert S, Chmiela MGenetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences.
Curr Top Microbiol Immunol. 2019; 421:53-76 [PubMed
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Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.
Wang Y, Wang G, Dong ZAssociation of X-ray cross-complementing group 3 Thr241Met gene polymorphism with osteosarcoma risk and its development and prognosis.
J Cancer Res Ther. 2018; 14(Supplement):S1178-S1182 [PubMed
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Aim of Study: The relationship between X-ray cross-complementing group 3 (XRCC3) Thr241Met gene polymorphism and osteosarcoma risk and its development and prognosis is still debated. This meta-analysis was performed to assess these associations.
Materials and Methods: The association studies were identified from PubMed, and eligible reports were included and calculated using meta-analysis method.
Results: Interestingly, all the included studies were from Asian population. The meta-analysis indicated that XRCC3 Thr241Met gene polymorphism was associated with osteosarcoma risk (T allele: Odds ratio [OR] =1.57, 95% confidence interval [CI]: 1.25-1.98, P = 0.0001; TT genotype: OR = 2.23, 95% CI: 1.40-3.57, P = 0.0008; CC genotype: OR = 0.69, 95% CI: 0.54-0.87, P = 0.002). However, XRCC3 Thr241Met CC genotype was not associated with Enneking stage, tumor location, and tumor metastasis.
Conclusion: XRCC3 Thr241Met gene polymorphism was associated with osteosarcoma risk, but XRCC3 Thr241Met CC genotype was not associated with Enneking stage, tumor location, and tumor metastasis.
BACKGROUND: In the past decade, accumulated evidence has suggested that genetic variation is related to the pathogenesis of osteosarcoma. Although there are a large number of studies on the association between genetic variation and osteosarcoma, their results are inconsistent. To clarify these findings, we performed a systematic meta-analysis using allelic contrasts for each gene-specific single nucleotide variants with all available data in the field of osteosarcoma.
METHODS: The literature search for relevant studies was conducted in PubMed, Embase, and Cochrane databases. Pooled ORs and 95% CI values were calculated by the random-effects model using the Comprehensive Meta-analysis version 2.0 software package. Heterogeneity between studies was examined by the Cochran's Q-test.
RESULTS: The 32 genome-wide case-control population-based studies, involving 15,336 study subjects (6924 cases and 8412 controls), were included in this meta-analysis. We analyzed 24 single nucleotide variants (SNVs) in 14 genes. We identified 12 SNVs in CTLA-4, IL-8, MDM2, PRCKG, RECQL5, TNF-a, TP53, XRCC3, and VEGF that correlated with osteosarcoma susceptibility. The average pooled odds ratio for the 9 risk alleles was 2.082 (range: 1.585 to 3.262). These included CTLA-4 rs231775, CTLA-4 rs5742909, PRCKG rs454006, RECQL5 rs820196, TNF-α rs1800629, TP53 rs1042522, XRCC3 rs861539, VEGF rs699947, and VEGF rs3025039. The average pooled odds ratio for the 3 protective alleles, IL-8 rs4073, MDM2 rs1690916, and VEGF rs2010963, was 0.606 (range: 0.510-0.719). Publication bias was not observed among the studies reporting positively correlated SNVs. The pooled odds ratios for the SNVs that correlated with osteosarcoma risk showed homogeneity.
CONCLUSION: Our results provide powerful information for tracking the most viable gene candidates. Further studies with larger multiethnicity populations and investigations of the potential biological roles of these genetic variants in osteosarcoma should be conducted.
Smolarz B, Michalska MM, Samulak D, et al.Studies of Correlations Between Single Nucleotide Polymorphisms of DNA Repair Genes and Endometrial Cancer in Polish Women.
Anticancer Res. 2018; 38(9):5223-5229 [PubMed
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AIM: The goals of this study included an analysis of the incidence of single nucleotide polymorphisms (SNPs) genotypes and alleles in DNA repair genes and evaluation of the effects by which this genetic variability may influence the risk for endometrial cancer.
MATERIALS AND METHODS: The study group included 610 women with endometrial cancer and was compared with a quantitatively matched control group of 610 women without any diagnosed malignancy. The following polymorphisms were analyzed: X-Ray repair cross complementing 1 (XRCC1)-Arg399Gln (rs25487); XRCC2-Arg188His (rs3218536); XRCC3-Thr241Met (rs861539); ERCC excision repair 2, TFIIH core complex helicase subunit (ERCC2)-Lys751Gln (rs13181); and 8-oxoguanine DNA glycosylase (OGG1)-Ser326Cys (rs13181).
RESULTS: Allele XRCC2-188His [odds ratio (OR)=5.24, 95% confidence interval (CI)=4.36-6.29; p<0.0001], hOGG1-326Cys (OR=1.60, 95% CI=1.36-1.88; p<0.0001) and ERCC2-751Gln (OR=1.67, 95% CI=1.42-1.96; p<0.0001) strongly correlated with neoplastic disease.
CONCLUSION: The evaluated SNPs may be approached as a group of new risk factors for the development of this cancer type.
Avadanei ER, Giusca SE, Negura L, Caruntu IDSingle nucleotide polymorphisms of XRCC3 gene in hepatocellular carcinoma - relationship with clinicopathological features.
Pol J Pathol. 2018; 69(1):73-81 [PubMed
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Recent studies support the involvement of XRCC3 gene polymorphisms in carcinogenesis. Our study focuses on the identification of polymorphic variants of XRCC3 in hepatocellular carcinoma (HCC) and an analysis of the relationship between these polymorphic variants and clinicopathological (including the genotype specific risk) and survival characteristics. Fifty cases of HCC were genotyped using molecular biology techniques for Thr241Met, rs861539 (c.722C>T) and 5'-UTR, rs1799796 (c.562-14A>G) polymorphisms. Statistical analysis was based on 2, Fisher's, logistic regression (odd ratio - OR), and log-rank tests. Statistically significant differences were shown only for rs1799796 A>G and tumour grade, between wild type (AA) and heterozygote (AG) genotypes, and wild type (AA) and heterozygote & homozygote (AG & GG) genotypes. The logistic regression analysis found an OR of rs1799796 polymorphism occurrence in HCC related to tumour grade. The statistical analysis revealed, for the rs861539 C>T polymorphism, a better survival only for the homozygote genotype (TT) compared to the heterozygote (CT), and for rs1799796 A>G polymorphism, a longer survival for the wild type (AA) compared to heterozygote (AG) and to heterozygote & homozygote (AG & GG) genotypes, respectively. Our results suggest that XRCC3 gene SNPs could influence the tumour aggressiveness expressed by tumour grade.
Roos WP, Frohnapfel L, Quiros S, et al.XRCC3 contributes to temozolomide resistance of glioblastoma cells by promoting DNA double-strand break repair.
Cancer Lett. 2018; 424:119-126 [PubMed
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Glioblastoma is the most frequent and aggressive form of high-grade malignant glioma. Due to the dismal prognosis faced by patients suffering from this disease, there is a need for identifying new targets that might improve therapy. The aim of this study was to determine the contribution of the DNA double-strand break (DSB) repair protein X-ray repair cross-complementing 3 (XRCC3) to the resistance of glioma cells to the chemotherapeutic drug temozolomide. Analysis of a publicly available database, E-GEOD-4290, showed that gliomas overexpress XRCC3 (NM_005432) compared to normal brain tissue. Using an isogenic glioma cell system, in which XRCC3 was downregulated by interference RNA, we demonstrate that XRCC3 protects glioma cells against temozolomide-induced reproductive cell death, apoptosis and cell cycle inhibition. Furthermore, XRCC3 knockdown significantly reduced the rate of repair of DSBs following TMZ treatment, which results in increased drug sensitivity. This study confirms the importance of homologous recombination in the resistance of glioma cells to the methylating drug temozolomide and adds XRCC3 to the list of homology-directed DNA repair proteins as possible targets for therapeutic intervention.
Liao WY, Ho CC, Tsai TH, et al.Combined effect of ERCC1 and ERCC2 polymorphisms on overall survival in non-squamous non-small-cell lung cancer patients treated with first-line pemetrexed/platinum.
Lung Cancer. 2018; 118:90-96 [PubMed
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OBJECTIVES: Polymorphisms of DNA repair genes may affect DNA repair capacity and the sensitivity of platinum doublets chemotherapy in non-small-cell lung cancer (NSCLC). We prospectively evaluated whether single nucleotide polymorphisms (SNPs) of ERCC1, ERCC2, XRCC1, and XRCC3 were associated with treatment outcome in advanced non-squamous NSCLC patients receiving pemetrexed/platinum as their first-line chemotherapy.
MATERIALS AND METHODS: Genotyping of six SNPs in four DNA repair genes in 58 patients treated with first-line pemetrexed/platinum was performed using TaqMan SNP Genotyping Assays.
RESULTS: The wild-type ERCC1 8092 (C/C) was significantly associated with a better objective response compared to the variant genotypes (C/A + A/A) (48% vs 10%, P = .005). In the multivariate Cox proportional hazards model, we found that individuals with a wild-type genotype of ERCC1 Asn118Asn, ERCC1 C8092A and ERCC2 Asp312Asn had significantly better overall survival (OS) than those with a heterozygous or homozygous variant genotype. On the other hand, the heterozygous variant genotype of ERCC2 Lys751Gln was associated with better OS than that of the wild-type genotype. We further explored the combined effect of SNPs on OS, and found a significant allele/dose-dependent trend toward decreasing OS in patients with an increasing number of unfavorable alleles among four SNPs in ERCC1 and ERCC2. The median OS of patients with two or three unfavorable alleles (30.1 and 30.5 months, respectively) was significantly longer than that of patients with 4 unfavorable alleles (11.8 months, log-rank test for trend, P = .001).
CONCLUSION: A combination of ERCC1 and ERCC2 polymorphisms may predict OS among pemetrexed/platinum treated advanced non-squamous NSCLC patients.
Devi KR, Ahmed J, Narain K, et al.DNA Repair Mechanism Gene, XRCC1A ( Arg194Trp) but not XRCC3 ( Thr241Met) Polymorphism Increased the Risk of Breast Cancer in Premenopausal Females: A Case-Control Study in Northeastern Region of India.
Technol Cancer Res Treat. 2017; 16(6):1150-1159 [PubMed
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X-ray repair cross complementary group gene is one of the most studied candidate gene involved in different types of cancers. Studies have shown that X-ray repair cross complementary genes are significantly associated with increased risk of breast cancer in females. Moreover, studies have revealed that X-ray repair cross complementary gene polymorphism significantly varies between and within different ethnic groups globally. The present case-control study was aimed to investigate the association of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer in females from northeastern region of India. The present case-control study includes histopathologically confirmed and newly diagnosed 464 cases with breast cancer and 534 apparently healthy neighborhood community controls. Information on sociodemographic factors and putative risk factors were collected from each study participant by conducting face-to-face interviews. Genotyping of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) was carried out by polymerase chain reaction-restriction fragment length polymorphism. For statistical analysis, both univariate and multivariate logistic regression analyses were performed. We also performed stratified analysis to find out the association of X-ray repair cross complementary genes with the risk of breast cancer stratified based on menstrual status. This study revealed that tryptophan allele (R/W-W/W genotype) in X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer (adjusted odds ratio = 1.44, 95% confidence interval = 1.06-1.97, P < .05 for R/W-W/W genotype). Moreover, it was found that tryptophan allele (W/W genotype) at codon 194 of X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer in premenopausal females (crude odds ratio = 1.66, 95% confidence interval = 1.11-2.46, P < .05 for R/W-W/W genotype). The present study did not reveal any significant association of X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer. The present study has explored that X-ray repair cross complementary 1A (Arg194Trp) gene polymorphism is significantly associated with the increased risk of breast cancer in premenopausal females from northeastern region of India which may be beneficial for prognostic purposes.
Pavanello S, Carta A, Mastrangelo G, et al.Relationship between Telomere Length, Genetic Traits and Environmental/Occupational Exposures in Bladder Cancer Risk by Structural Equation Modelling.
Int J Environ Res Public Health. 2017; 15(1) [PubMed
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RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have recently been involved in breast and ovarian cancer predisposition: RAD51B, RAD51C, and RAD51D in ovarian cancer, RAD51B and XRCC2 in breast cancer. The aim of this study was to estimate the contribution of deleterious variants in the five RAD51 paralogs to breast and ovarian cancers. The five RAD51 paralog genes were analyzed by next-generation sequencing technologies in germline DNA from 2649 consecutive patients diagnosed with breast and/or ovarian cancer. Twenty-one different deleterious variants were identified in the RAD51 paralogs in 30 patients: RAD51B (n = 4), RAD51C (n = 12), RAD51D (n = 7), XRCC2 (n = 2), and XRCC3 (n = 5). The overall deleterious variant rate was 1.13% (95% confidence interval (CI): 0.72-1.55%) (30/2649), including 15 variants in breast cancer only cases (15/2063; 0.73% (95% CI: 0.34-1.11%)) and 15 variants in cases with at least one ovarian cancer (15/570; 2.63% (95% CI: 1.24-4.02%)). This study is the first evaluation of the five RAD51 paralogs in breast and ovarian cancer predisposition and it demonstrates that deleterious variants can be present in breast cancer only cases. Moreover, this is the first time that XRCC3 deleterious variants have been identified in breast and ovarian cancer cases.
Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, et al.Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer.
Pathol Res Pract. 2018; 214(1):44-52 [PubMed
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Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC. No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.
The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc. We established and characterized the IM-resistant GIST T-1 cell line (GIST T-1R) lacking secondary c-KIT mutations typical for the IM-resistant phenotype. The resistance to IM in GIST T-1R cells was due to RTK switch (loss of c-KIT/gain of FGFR2α). Indeed, we have found that FGFR inhibition reduced cellular viability, induced apoptosis and affected the growth kinetics of the IM-resistant GISTs in vitro. In contrast, IM-naive GIST T-1 parental cells were not susceptible to FGFR inhibition. Importantly, inhibition of FGF-signaling restored the susceptibility to IM in IM-resistant GISTs. Additionally, IM-resistant GISTs were less susceptible to certain chemotherapeutic agents as compared to parental IM-sensitive GIST cells. The chemoresistance in GIST T-1R cells is not due to overexpression of ABC-related transporter proteins and might be the result of upregulation of DNA damage signaling and repair (DDR) genes involved in DNA double-strand break (DSB) repair pathways (e.g., XRCC3, Rad51, etc.). Taken together, the established GIST T-1R cell subline might be used for in vitro and in vivo studies to examine the efficacy and prospective use of FGFR inhibitors for patients with IM-resistant, un-resectable and metastatic forms of GISTs with the type of RTK switch indicated above.
Ahmed T, Nawaz S, Noreen R, et al.A 3' untranslated region polymorphism rs2304277 in the DNA repair pathway gene OGG1 is a novel risk modulator for urothelial bladder carcinoma.
Ann Hum Genet. 2018; 82(2):74-87 [PubMed
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Altered DNA repair capacity may affect an individual's susceptibility to cancers due to compromised genomic integrity. This study was designed to elucidate the association of selected polymorphisms in DNA repair genes with urothelial bladder carcinoma (UBC). OGG1 rs1052133 and rs2304277, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs2228001, and XPD rs13181 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 200 UBC cases and 200 controls. We found association of OGG1 rs2304277 [odds ratio (OR)
AIM: To uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians.
METHODS: The present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two, independent, HCC-free, age/sex-matched control groups. The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation. The first control group comprised 167 patients that were matched to the HCC cohort for the percentage of hepatitis B (HBV) and/or hepatitis C (HCV) infections. A second control group included 192 virus-free, healthy individuals that were used to evaluate the generalizability of the identified predictive markers. All cases and controls were Caucasian. The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways. The study end-point was to assess the association between genetic variants and HCC onset.
RESULTS: Five genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV. According to a dominant model, reduced HCC risk was associated with three polymorphisms:
CONCLUSION: We identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management.
Özgöz A, Hekimler Öztürk K, Yükseltürk A, et al.Genetic Variations of DNA Repair Genes in Breast Cancer.
Pathol Oncol Res. 2019; 25(1):107-114 [PubMed
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Genetic variations in DNA repair genes may affect DNA repair capacity therefore increase risk for cancer. In our study, we evaluted the relation between DNA repair gene polymorphisms XRCC1 rs1799782, rs25487, rs25489; XPC rs2228000, rs2228001; XPD rs1799793, rs13181; XRCC3 rs861539; RAD51B rs10483813, rs1314913 and breast cancer risk for 202 Turkish cases in total, in which 102 patients with breast cancer and 100 controls. Genotyping of the DNA samples was carried out by multiplex PCR and matrix-assisted laser desorption/ionization mass spectrometry with time of flight measurement (MALDI-TOF) using Sequenom MassARRAY 4 analyzer. Genotype and allele distributions were calculated between the groups. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. rs25487 AA genotype and A allele was found to be increased in the control group (respectively, OR 0.16 95% CI 0.02-1.06, p = 0.058; OR 1.55, 95% CI 1.01-2.36, p = 0.043) and rs861539 T allele was found to be decreased in the patient group (OR 1.53, 95% CI 1.01-2.30, p = 0.049). No association with breast cancer was found for the remaining SNPs. Our findings suggest that XRCC1 rs25487 AA genotype and A allele, XRCC3 rs861539 T allele may have protective effects in breast cancer for Turkish population.
Silva-Fernandes IJL, Oliveira ES, Santos JC, et al.The intricate interplay between MSI and polymorphisms of DNA repair enzymes in gastric cancer H.pylori associated.
Mutagenesis. 2017; 32(4):471-478 [PubMed
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Gastric cancer is the fourth most common type of cancer worldwide. Helicobacter pylori is a well-established risk factor and may cause injuries to genomic integrity through an inefficient DNA repair. This study aimed to examine the influence of polymorphisms in DNA repair enzymes using markers for microsatellite instability (MSI). Polymorphisms of DNA repair enzymes were detected by PCR-RFLP and MSI, by high resolution melt (HRM) analysis. Helicobacter pylori detection and genotyping were accomplished by PCR. MSI was observed in 47.5% of the cases and it was associated with the ERCC1 polymorphic allele, whereas MSI-H was associated with the XRCC3 heterozygous genotype. MSI was more frequent in intestinal gastric cancer (IGC), where it was associated with ERCC1 or RAD51 polymorphic alleles. Also, MSI-H was associated with the XRCC3 heterozygous. In diffuse gastric cancer (DGC), almost all of MGMT polymorphic genotype carriers showed MSI. Helicobacter pylori was positive in 94% of the cases and the most virulent strains were associated with MSI, mainly MSI-H. When the subtypes were considered, these associations were found only in the IGC and associated with more virulent strains. Among the cases with microsatellite instability, IGC showed a correlation between the XPD wild-type and the ERCC1 polymorphic allele, and all of them were infected by the most virulent strains. On the other hand, in DGC, the XPD polymorphic allele was correlated with the XRCC3 wild-type with no prevalence of H.pylori virulence. Our data demonstrated that polymorphisms in repair enzymes can interfere with the efficiency of the repair process, but it differs depending on the histological subtype and H.pylori involvement. Besides nucleotide excision repair, base excision repair and mismatch repair pathway, the homologous recombination are also involved.
Al-Harbi NM, Bin Judia SS, Mishra KN, et al.Genetic Predisposition to Cervical Cancer and the Association With XRCC1 and TGFB1 Polymorphisms.
Int J Gynecol Cancer. 2017; 27(9):1949-1956 [PubMed
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OBJECTIVE: Cervical carcinoma (CC), a multifactorial cancer, is assumed to have a host genetic predisposition component that modulates its susceptibility in various populations. We investigated the association between CC risk in Saudi women and 6 single-nucleotide polymorphisms (SNPs) in hypothesis-driven candidate genes.
METHODS: A total of 545 females were included, comprising 232 CC patients and 313 age-/sex-matched control subjects. Six SNPs (CDKN1A C31A, ATM G1853A, HDM2 T309G, TGFB1 T10C, XRCC1 G399A, and XRCC3 C241T) were genotyped by direct sequencing.
RESULTS: Of the 6 SNPs studied, TGFB1 T10C (odds ratio, 0.74; 95% confidence interval, 0.57-0.94) and XRCC1 G399A (odds ratio, 1.45; 95% confidence interval, 1.11-1.90) displayed different frequencies in cancer patients and control subjects and showed statistically significant association in univariate (P = 0.017, P = 0.005, respectively) analysis. The Cochran-Armitage trend test had confirmed the results (P = 0.027 and P = 0.006, respectively), indicating an ordering in the effect of the risk alleles in CC patients. The 2 SNPs, TGFB1 T10C and XRCC1 G399A, showed also degrees of deviation from Hardy-Weinberg equilibrium in cancer patients (P = 0.001 and P = 0.083, respectively) but not in the control subjects. Furthermore, correction for multiple testing using multivariate logistic regression to assess the joint effect of all SNPs has sustained significant statistical association (P = 0.025 and P = 0.009, respectively).
CONCLUSIONS: TGFB1 T10C and XRCC1 G399A SNPs were associated with CC risk in univariate and multivariate analysis and displayed allele-dosage effects and coselection in cancer patients. Patients harboring the majority allele TGFB1 T10 (Leu) or the variant allele XRCC1 399A (Gln) have approximately 1.5-fold increased risk to develop CC. Host SNPs genotyping may provide relevant biomarkers for CC risk assessment in personalized preventive medicine.
African-American women are more likely to develop aggressive breast cancer at younger ages and experience poorer cancer prognoses than non-Hispanic Caucasians. Deficiency in repair of DNA by homologous recombination (HR) is associated with cancer development, suggesting that mutations in genes that affect this process may cause breast cancer. Inherited pathogenic mutations have been identified in genes involved in repairing DNA damage, but few studies have focused on African-Americans. We screened for germline mutations in seven HR repair pathway genes in DNA of 181 African-American women with breast cancer, evaluated the potential effects of identified missense variants using in silico prediction software, and functionally characterized a set of missense variants by yeast two-hybrid assays. We identified five likely-damaging variants, including two PALB2 truncating variants (Q151X and W1038X) and three novel missense variants (RAD51C C135R, and XRCC3 L297P and V337E) that abolish protein-protein interactions in yeast two-hybrid assays. Our results add to evidence that HR gene mutations account for a proportion of the genetic risk for developing breast cancer in African-Americans. Identifying additional mutations that diminish HR may provide a tool for better assessing breast cancer risk and improving approaches for targeted treatment.
Hsueh YM, Lin YC, Chen WJ, et al.The polymorphism XRCC1 Arg194Trp and 8-hydroxydeoxyguanosine increased susceptibility to arsenic-related renal cell carcinoma.
Toxicol Appl Pharmacol. 2017; 332:1-7 [PubMed
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This study was designed to explore the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms and renal cell carcinoma (RCC) and to investigate whether individuals with an XRCC1 risk genotype, a high level of 8-OHdG or a high urinary total arsenic concentration have a modified odds ratio (OR) of RCC. We recruited 180 RCC patients and 360 age- and sex-matched controls from a hospital-based pool. Image-guided biopsy or surgical resection of renal tumors was performed on RCC patients for pathological verification. Genomic DNA was used to examine the genotype of XRCC1(Arg399Gln), XRCC1(Arg194Trp), XRCC3(Thr241Met) and XPD(Lys751Gln) by PCR-RFLP. Liquid chromatography with tandem mass spectrometry was used to determine urinary 8-OHdG levels. A HPLC-HG-AAS was used to determine the concentrations of urinary arsenic species. Participants with the genotype XRCC1(Arg194Trp) Arg/Trp+Trp/Trp had a significantly higher OR of RCC than those with the Arg/Arg genotype; the OR and 95% confidence interval was 0.66 (0.45-0.97) after multivariate adjustment. The OR of RCC for the combined effect of high urinary 8-OHdG levels and high urinary total arsenic concentration in individuals with a XRCC1(Arg194Trp) Arg/Trp+Trp/Trp genotype was higher than in patients with an Arg/Arg genotype, which was evident in a dose response manner. In conclusion, this is the first study to show that the XRCC1 Arg194 allele is a predicting factor for RCC. The more risk factors (high urinary 8-OHdG levels, high urinary total arsenic concentrations, and XRCC1 Arg194 allele) that were present, the higher the OR of RCC.
Tan LM, Qiu CF, Zhu T, et al.Genetic Polymorphisms and Platinum-based Chemotherapy Treatment Outcomes in Patients with Non-Small Cell Lung Cancer: A Genetic Epidemiology Study Based Meta-analysis.
Sci Rep. 2017; 7(1):5593 [PubMed
] Free Access to Full Article Related Publications
Data regarding genetic polymorphisms and platinum-based chemotherapy (PBC) treatment outcomes in patients with NSCLC are published at a growing pace, but the results are inconsistent. This meta-analysis integrated eligible candidate genes to better evaluate the pharmacogenetics of PBC in NSCLC patients. Relevant studies were retrieved from PubMed, Chinese National Knowledge Infrastructure and WANFANG databases. A total of 111 articles comprising 18,196 subjects were included for this study. The associations of genetic polymorphisms with treatment outcomes of PBC including overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) were determined by analyzing the relative risk (RR), hazard ration (HR), corresponding 95% confidence interval (CI). Eleven polymorphisms in 9 genes, including ERCC1 rs11615 (OS), rs3212986 (ORR), XPA rs1800975 (ORR), XPD rs1052555 (OS, PFS), rs13181 (OS, PFS), XPG rs2296147 (OS), XRCC1 rs1799782 (ORR), XRCC3 rs861539 (ORR), GSTP1 rs1695 (ORR), MTHFR rs1801133 (ORR) and MDR1 rs1045642 (ORR), were found significantly associated with PBC treatment outcomes. These variants were mainly involved in DNA repair (EXCC1, XPA, XPD, XPG, XRCC1 and XRCC3), drug influx and efflux (MDR1), metabolism and detoxification (GSTP1) and DNA synthesis (MTHFR), and might be considered as potential prognostic biomarkers for assessing objective response and progression risk in NSCLC patients receiving platinum-based regimens.
Soares S, Nogueira A, Coelho A, et al.Relationship between clinical toxicities and ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms in cervical cancer patients.
Int J Biol Markers. 2018; 33(1):116-123 [PubMed
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BACKGROUND: Several studies have suggested that there are single nucleotide polymorphisms (SNPs) that can be considered potential biomarkers in the prognosis and therapeutic response of cancer patients. The present study investigated the association between ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms and clinical toxicities induced by chemoradiotherapy (CRT) in cervical cancer.
METHODS: This hospital-based retrospective cohort study included 260 patients with cervical cancer, FIGO stages Ib2-IVa, who underwent CRT (cisplatin). Genetic polymorphisms analysis was performed by allelic discrimination with real-time polymerase chain reaction (RT-PCR).
RESULTS: Our results indicated a link between ERCC1 rs3212986 and the onset of late gastrointestinal toxicity (p = 0.038). Furthermore, using a recessive model (AA vs. CC/CA), we found that patients carrying AA homozygous genotype presented a fourfold increased risk of developing late gastrointestinal toxicity when compared with patients with the C allele (odds ratio = 3.727, 95% confidence interval, 1.199-11.588; p = 0.017). No association was found regarding the XRCC3 rs861539 polymorphism and any clinical toxicity event.
CONCLUSIONS: This is the first study evaluating the relationship between these polymorphisms and clinical toxicities in cervical cancer patients submitted to CRT with cisplatin. These results may contribute toward a better understanding of the influence of genetic polymorphisms in genes associated with DNA repair in the clinical response to CRT of patients with cervical cancer.
Avci H, Ergen A, Bireller ES, et al.A Strong Relationship Between Oral Squamous Cell Carcinoma and DNA Repair Genes.
Biochem Genet. 2017; 55(5-6):378-386 [PubMed
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Single nucleotide polymorphisms of DNA repair genes alter protein function and modulate DNA repair efficiency in various cancers. The X-ray repair cross-complementing group (XRCC) is responsible for the repair of DNA base damage and single-strand breaks. The aim of our study was to investigate the association of XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms with the susceptibility to develop oral squamous cell carcinoma (OSCC) in Turkish subjects. One hundred eleven patients with OSCC and 148 healthy controls were recruited for the study. Genetic analysis was performed using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). We found that the XRCC1 Arg399Gln Gln/Gln genotype and Gln allele were risk factors for OSCC. Also, Arg/Arg genotype and Arg allele had protective effects against OSCC. Relative to XRCC3 Thr241Met polymorphism, carrying homozygote variants (Thr/Thr and Met/Met) was related with elevated OSCC risk. However, the heterozygote genotype and Thr allele variants were shown to be protective against OSCC. We suggest that XRCC1 Arg399Gln Gln/Gln genotype, Gln allele, and homozygote variants of XRCC3 Thr241Met polymorphism may be a risk factor for predisposition of OSCC in Turkish. In addition, XRCC3 Thr241Met genotype could be associated with tumor size and level of daily smoking.
Normando AGC, Rocha CL, de Toledo IP, et al.Biomarkers in the assessment of oral mucositis in head and neck cancer patients: a systematic review and meta-analysis.
Support Care Cancer. 2017; 25(9):2969-2988 [PubMed
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PURPOSE: The aim of this study was to evaluate the capability of biomarkers to predict the risk of oral mucositis in head and neck cancer patients, as well as to assess the correlation between these biomarkers and the severity of mucositis.
METHODS: The search was performed at LILACS, PubMed, Science Direct, Scopus, and Web of Science. A search of the gray literature was performed on Google Scholar, OpenGrey, and ProQuest. The methodological quality of the included studies was assessed using the Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) tool, and the evidence quality was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system.
RESULTS: After a two-step selection process, 26 studies met the eligibility criteria. In total, 27 biomarkers were evaluated, and the most frequent were the epidermal growth factor (EGF), C-reactive protein (CRP), genetic polymorphisms, tumor necrosis factor alpha (TNF-α), and erythrocyte sedimentation rate (ESR). The meta-analysis showed an expression of polymorphisms in XRCC1 (32.66%), XRCC3 (31.00%), and RAD51 (39.16%) genes, as well as an expression of protein biomarkers (39.57%), in patients with an increased risk of developing oral mucositis.
CONCLUSIONS: Dosing biomarkers before starting radiation therapy may be a promising method to predict the risk of developing mucositis and allow radiosensitive patients to have a customized treatment. Although there is currently limited evidence to confirm the putative implementation of serum and salivary biomarkers to assess the correlation between them and the severity of mucositis, this current review provides new research directions.
Krupa R, Czarny P, Wigner P, et al.The Relationship Between Single-Nucleotide Polymorphisms, the Expression of DNA Damage Response Genes, and Hepatocellular Carcinoma in a Polish Population.
DNA Cell Biol. 2017; 36(8):693-708 [PubMed
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The molecular mechanism of hepatocellular carcinoma (HCC) is related to DNA damage caused by oxidative stress products induced by hepatitis B virus (HBV) or C (HCV) infection and exposure to environmental pollutants. Single-nucleotide polymorphisms (SNPs) of DNA damage response (DDR) genes may influence individual susceptibility to environmental risk factors and affect DNA repair efficacy, which, in turn, can influence the risk of HCC. The study evaluates a panel of 15 SNPs in 11 DDR genes (XRCC1, XRCC3, XPD, MUTYH, LIG1, LIG3, hOGG1, PARP1, NFIL1, FEN1, and APEX1) in 65 HCC patients, 50 HBV- and 50 HCV-infected non-cancerous patients, and 50 healthy controls. It also estimates the mRNA expression of nine DDR genes in cancerous and adjacent healthy liver tissues. Two of the investigated polymorphisms (rs1052133 and rs13181) were associated with HCC risk. For all investigated genes, the level of mRNA was significantly lower in HCC cancer tissue than in non-cancerous liver tissue. Seven of the investigated polymorphisms were statistically related to gene expression in cancer tissues. The disruption of DDR genes may be responsible for hepatocellular transformation in HCV-infected patients.
Yu SN, Liu GF, Li XF, et al.Evaluation of Prediction of Polymorphisms of DNA Repair Genes on the Efficacy of Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer: A Network Meta-Analysis.
J Cell Biochem. 2017; 118(12):4782-4791 [PubMed
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This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820), and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation. This network meta-analysis combines direct and indirect evidence to assess the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC. We evaluated the predictive value through the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). A total of 26 eligible cohort studies were enrolled in this NMA. The pairwise meta-analysis indicated that in terms of overall response ratio (ORR), ERCC1 (rs11615), XRCC1 (rs25487, rs1799782), and XPD (rs13181) polymorphisms are associated with the efficacy of platinum-based chemotherapy in NSCLC. The result of this NMA suggests that there is no significant difference in predictive value of 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC patients. The rank of SUCRA values of the 14 SNPs in the eight DNA repair genes were: XPD (rs1799793)→ERCC1 (rs3212986)→XPA(rs1800975)→ERCC1(rs3212948)→XRCC1(rs25487)→XRCC3(rs861539)→APE1(rs3136820)→ERCC1(rs11615)→XRCC1(rs1799782)→RRM1(rs1042858)→XPD(rs13181)→XPG (rs1047768)→XPG(rs17655)→XRCC1(rs25489). ERCC1(rs11615), XRCC1(rs25487, rs1799782) and XPD(rs13181) polymorphisms were better predictors in evaluating the efficacy of platinum-based chemotherapy in NSCLC patients. J. Cell. Biochem. 118: 4782-4791, 2017. © 2017 Wiley Periodicals, Inc.
Sarwar R, Mahjabeen I, Bashir K, et al.Haplotype Based Analysis of XRCC3 Gene Polymorphisms in Thyroid Cancer.
Cell Physiol Biochem. 2017; 42(1):22-33 [PubMed
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BACKGROUND/AIMS: In mammalian cells, XRCC3 plays an important role in the DNA double-strand breaks (DSBs) repair by homologous recombination. Genetic polymorphisms in XRCC3 gene may potentially affect the repair of DSBs and thus confer susceptibility to thyroid cancer. In this study, we used a haplotype-based approach to investigate whether 5 selected SNPs i.e. rs1799796, rs1799794, rs861539, rs709399 and rs861530 of XRCC3 gene are associated with thyroid cancer risk in 456 cancer patients and 400 cancer-free controls.
METHODS: Genotyping was performed using Allele-specific PCR followed by sequencing. Statistical analysis was performed to analyse gene and haplotype association.
RESULTS: After analysis, frequency of mutant genotype/alleles of SNPs (rs1799796, p<0.0001; rs1799794, p<0.0001; rs861539, p<0.001; rs709399, p <0.0001; rs861530, p<0.002) was found significantly higher in thyroid cancer patients compared to controls. Significant associations were found for most of the variant genotypes in SNPs of rs1799794, rs1799796, rs861539, rs861530 and rs709399 in papillary thyroid and follicular cancer patients compared to other histologic subtypes of thyroid carcinoma. Additionally, haplotype analysis revealed that haplotypes, AACGA (p= 0.0005), AGTAA (p= 0.008), GATAA (p= 0.001), GGCAA (p= 0.001) were linked with significant increase in thyroid cancer risk. However, haplotype AGCGG (p= 0.0009) was associated with a significant reduced thyroid cancer risk.
CONCLUSION: Our results suggest that common genetic variants in the XRCC3 gene of DSBR pathway may modulate thyroid cancer risk.
Background: Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102.
Patients and methods: We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct sequencing.
Results: In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival (OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14-0.99, P = 0.022). Patients carrying any A allele in XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21-0.92, P = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATM rs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical significance.
Conclusion: Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.
Variations in DNA repair genes have been reported as key factors in gastric cancer (GC) susceptibility but results among studies are inconsistent. We aimed to assess the relevance of DNA repair gene polymorphisms and environmental factors to GC risk and phenotype in a Caucasian population in Spain. Genomic DNA from 603 patients with primary GC and 603 healthy controls was typed for 123 single nucleotide polymorphisms in DNA repair genes using the Illumina platform. Helicobacter pylori infection with CagA strains (odds ratio (OR): 1.99; 95% confidence interval (CI): 1.55-2.54), tobacco smoking (OR: 1.77; 95% CI: 1.22-2.57), and family history of GC (OR: 2.87; 95% CI: 1.85-4.45) were identified as independent risk factors for GC. By contrast, the TP53 rs9894946A (OR: 0.73; 95% CI: 0.56-0.96), TP53 rs1042522C (OR: 0.76; 95% CI: 0.56-0.96), and BRIP1 rs4986764T (OR: 0.55; 95% CI: 0.38-0.78) variants were associated with lower GC risk. Significant associations with specific anatomopathological GC subtypes were also observed, most notably in the ERCC4 gene with the rs1799801C, rs2238463G, and rs3136038T variants being inversely associated with cardia GC risk. Moreover, the XRCC3 rs861528 allele A was significantly increased in the patient subgroup with diffuse GC (OR: 1.75; 95% CI: 1.30-2.37). Our data show that specific TP53, BRIP1, ERCC4, and XRCC3 polymorphisms are relevant in susceptibility to GC risk and specific subtypes in Caucasians.
Procopciuc LM, Osian G, Iancu MColorectal Cancer Carcinogenesis: a Multivariate Genetic Model in a Cohort of Romanian Population.
Clin Lab. 2017; 63(4):647-658 [PubMed
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BACKGROUND: The molecular mechanism of carcinogenesis of sporadic colorectal cancer (CRC) involves genes with roles in folate metabolism, genes involved in metabolization of carcinogenic compounds from diet and tobacco smoke, and genes related to the DNA repair process. The aim of the study was to examine whether the MTHFRC677T, MTHFR- A1298C, TS-2rpt/3rpt, TS-1494del6bp, NAT2*5C-C481T, NAT2*5A-T341C, NAT2*6B-G590A, NAT2*7B-G857A, NAT2*18-A845C, GSTM1-null, XRCC1-Arg399Gln, XRCC3-Thr241Met, XPD-Lys751Gln genetic variations are associated with CRC prognosis, in the presence of environmental and demographic factors.
METHODS: We genotyped 150 patients diagnosed with sporadic CRC using PCR-RFLP and sequencing methods. The performance of the final model was quantified using Nagelkerke's coefficient, the Hosmer-Lemeshow test, C statistics, and Somers' (D) index, capable of describing the model's goodness-of-fit and discrimination.
RESULTS: Multiple logistic regression analysis established a significant independent association of NAT2*18-A845C, MTHFR-C677T, XRCC3-Thr241Met, NAT2*7B-G857A, XPD-Lys751Gln, XRCC1-Arg399Gln and NAT2*6BG590A with an increased prevalence of sporadic CRC, regardless of the presence/absence of colonic tumors. After an adjustment for other polymorphisms and environmental risk factors, the risk to develop sporadic CRC was 2.25 (p = 0.011) and 2.31 (p = 0.01) in association with the NAT2*18-A845C and MTHFR-C677T genetic variants, respectively. The risk increased to 3.22 (p = 0.0005) and 3.69 (p = 0.0009) in association with the XRCC3Thr241Met and NAT2*7B-G857A polymorphisms. Also, patients carrying the XPD-Lys751Gln, XRCC1Arg399Gln, and NAT2*6B-G590A polymorphisms had a 4.16 (p < 0.0001), 5.16 (p < 0.0001), and 5.46-fold (p < 0.0001) increased risk for sporadic CRC, under the dominant genetic comparison model. In addition, we found an interaction between gender and alcohol, the effect of alcohol consumption on the risk of developing sporadic CRC being different in female and male patients.
CONCLUSIONS: Our study confirmed the predictive role of some polymorphisms associated with DNA methylation and procarcinogen transformation into carcinogenic compounds in sporadic CRC risk and, also, the influence of environmental risk factors such as diet, smoking, and alcohol consumption on this association.
Pérez-Ramírez C, Cañadas-Garre M, Molina MÁ, et al.Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer.
Mutat Res. 2017 Jan - Mar; 771:32-58 [PubMed
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Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-β pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-β, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.