BLM and RAD51 genes polymorphism and susceptibility to breast cancer.
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ABSTRACT:
SUBMITTER: Sassi A
PROVIDER: S-EPMC3708281 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.
| S-EPMC3459953 | biostudies-literature
Project description:Leptin is a confirmed breast cancer susceptibility gene. However, published studies reported mixed results. This meta-analysis was conducted to systematically get a more accurate estimation of the association between the Leptin (-2548G/A) gene polymorphism and breast cancer risk. To assess the effect of Leptin (-2548G/A) gene polymorphism on breast cancer susceptibility, we searched PUBMED, ISI Web of Knowledge, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases until September 2015 to identify eligible studies, without restriction. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to breast cancer. Separate analyses were conducted on features of the population such as ethnicity, source of controls, and country. A total of 9 case-control studies on Leptin (-2548G/A) gene polymorphism and breast cancer risk, including 3725 cases and 3093 case-free controls were identified. The results revealed that compared with the G allele, the A allele was associated with modestly increased risk of overall breast cancer (A vs G: OR = 1.12, 95%CI = 1.04-1.20, P = 0.002, Phet P < 0.00001). Following further stratified analyses, in the subgroup analyses by ethnicity, a significantly increased risk was observed among Caucasian (A vs G: OR = 1.11, 95%CI = 1.03-1.20, P = 0.006, Phet = 0.00001). No publication bias was found in the present study. In conclusion, our meta-analysis suggests that the Leptin (-2548G/A) gene polymorphism plays an important role in breast cancer susceptibility, especially in Caucasian.
| S-EPMC5291568 | biostudies-literature
Project description:BackgroundAlthough inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.Methodology/principal findingsWe screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery.ConclusionAltogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.
| S-EPMC3531476 | biostudies-literature
Project description:BackgroundPathogenic variants in cancer susceptibility genes can increase the risk of a spectrum of diseases, which clinicians must manage for their patients. We evaluated the disease spectrum of breast cancer susceptibility genes (BCSGs) with the aim of developing a comprehensive resource of gene-disease associations for clinicians.MethodsTwelve genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RECQL, STK11, and TP53), all of which have been conclusively established as BCSGs by the Clinical Genome Resource (ClinGen) and/or the NCCN guidelines, were investigated. The potential gene-disease associations for these 12 genes were verified and evaluated based on six genetic resources (ClinGen, NCCN, OMIM, Genetics Home Reference, GeneCards, and Gene-NCBI) and an additional literature review using a semiautomated natural language processing (NLP) abstract classification procedure.ResultsForty-two diseases were found to be associated with one or more of the 12 BCSGs for a total of 86 gene-disease associations, of which 90% (78/86) were verified by ClinGen and/or NCCN. Four gene-disease associations could not be verified by either ClinGen or NCCN but were verified by at least three of the other four genetic resources. Four gene-disease associations were verified by the NLP procedure alone.ConclusionThis study is unique in that it systematically investigates the reported disease spectrum of BCSGs by surveying multiple genetic resources and the literature with the aim of developing a single consolidated, comprehensive resource for clinicians. This innovative approach provides a general guide for evaluating gene-disease associations for BCSGs, potentially improving the clinical management of at-risk individuals.
| S-EPMC8093501 | biostudies-literature
Project description:BACKGROUND:The HER2 (human epidermal growth factor receptor-2) Ile655Val (rs1136201) genetic polymorphism can alter the receptor structure and its auto-activation, which can modify the signal transduction and, consequently, the cell cycle regulation. For this reason, this polymorphism has been extensively investigated as a candidate marker for breast cancer (BC). In this context, the aim of this study was to evaluate the possible influence of HER2 Ile655Val in BC susceptibility and prognostic factors in a Brazilian population. METHODS:Polymorphism genotype was assessed through RFLP-PCR in 107 BC patients with clinicopathological data available and in 150 women with no evidence of neoplasia and with no familial history of BC as control group. Association between this polymorphism and BC susceptibility and clinical parameters was evaluated through odds ratio (OR) and chi-squared or Fisher's exact test, respectively. RESULTS:A significant negative association between valine allele and BC susceptibility in dominant model was found (OR 0.5; 95% CI 0.27-0.93, P = .036). No significant association was found in relation to BC clinicopathological features (tumor size, lymph nodes commitment, histological grade, HER2 overexpression, hormonal receptors, p53, and Ki-67). CONCLUSION:Although this polymorphism did not demonstrate potential as a prognostic marker, it may be a suitable susceptibility marker for BC.
| S-EPMC6817048 | biostudies-literature
Project description:Inter-individual variation in DNA repair capacity is thought to modulate breast cancer risk. The phenotypic mutagen sensitivity assay (MSA) measures DNA strand breaks in lymphocytes; women with familial and sporadic breast cancers have a higher mean number of breaks per cell (MBPC) than women without breast cancer. Here, we explore the relationships between the MSA and the Rad51 gene, which encodes a DNA repair enzyme that interacts with BRCA1 and BRCA2, in BRCA1 mutation carriers and women with sporadic breast cancer.Peripheral blood lymphoblasts from women with known BRCA1 mutations underwent the MSA (n = 138 among 20 families). BRCA1 and Rad51 genotyping and sequencing were performed to identify SNPs and haplotypes associated with the MSA. Positive associations from the study in high-risk families were subsequently examined in a population-based case-control study of breast cancer (n = 1170 cases and 2115 controls).Breast cancer diagnosis was significantly associated with the MSA among women from BRCA1 families (OR = 3.2 95%CI: 1.5-6.7; p = 0.004). The Rad51 5'UTR 135 C>G genotype (OR = 3.64; 95% CI: 1.38, 9.54; p = 0.02), one BRCA1 haplotype (p = 0.03) and in a polygenic model, the E1038G and Q356R BRCA1 SNPs were significantly associated with MBPC (p = 0.009 and 0.002, respectively). The Rad51 5'UTR 135C genotype was not associated with breast cancer risk in the population-based study.Mutagen sensitivity might be a useful biomarker of penetrance among women with BRCA1 mutations because the MSA phenotype is partially explained by genetic variants in BRCA1 and Rad51.
| S-EPMC3146938 | biostudies-literature
Project description:AimThe aim of the study was to determine the relationship between single nucleotide polymorphisms (SNPs) of DNA repair genes and modulation of the risk of breast cancer. The following SNPs were analysed: XRCC1-Arg399Gln (rs25487), hMSH2-Gly322Asp (rs4987188), XRCC2-Arg188His (rs3218536), XPD- Lys751Gln (rs13181), RAD51--4719A/T (rs2619679) and RAD51--4601A/G (rs5030789).Material and methodsThe study included n = 600 patients: 300 with breast cancer and 300 healthy controls. The HRM (High-Resolution Melter) technique was applied for polymorphism analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.ResultsStatistically significant correlations were identified between four single nucleotide polymorphisms and the breast cancer risk: XRCC1-Arg399Gln, hMSH2-Gly322Asp, XPD- Lys751Gln and RAD51--4719A/T. Allele XRCC1-Gln (OR 6.37; 95% CI 4.86-8.35, p < .0001), hMSH2-Asp (OR 4.41; 95% CI 3.43-5.67, p < .0001), XPD -Gln (OR 2.56; 95% CI 2.02-3.25, p < .0001) and RAD51-T genes (OR 1.44; 95% CI 1.15-1.80, p = 0.002) strongly correlated with breast carcinoma. No relationship was observed between the studied polymorphisms and the cancer progression grade according to Scarf-Bloom-Richardson classification.ConclusionsThe results implies that polymorphisms of DNA repair genes may be associated with breast cancer occurrence.
| S-EPMC6355183 | biostudies-literature
Project description:The gene mutated in Bloom's syndrome, BLM, is important in the repair of damaged replication forks, and it has both pro- and anti-recombinogenic roles in homologous recombination (HR). At damaged forks, BLM interacts with RAD51 recombinase, the essential enzyme in HR that catalyzes homology-dependent strand invasion. We have previously shown that defects in BLM modification by the small ubiquitin-related modifier (SUMO) cause increased gamma-H2AX foci. Because the increased gamma-H2AX could result from defective repair of spontaneous DNA damage, we hypothesized that SUMO modification regulates BLM's function in HR repair at damaged forks. To test this hypothesis, we treated cells that stably expressed a normal BLM (BLM+) or a SUMO-mutant BLM (SM-BLM) with hydroxyurea (HU) and examined the effects of stalled replication forks on RAD51 and its DNA repair functions. HU treatment generated excess gamma-H2AX in SM-BLM compared to BLM+ cells, consistent with a defect in replication-fork repair. SM-BLM cells accumulated increased numbers of DNA breaks and were hypersensitive to DNA damage. Importantly, HU treatment failed to induce sister-chromatid exchanges in SM-BLM cells compared to BLM+ cells, indicating a specific defect in HR repair and suggesting that RAD51 function could be compromised. Consistent with this hypothesis, RAD51 localization to HU-induced repair foci was impaired in SM-BLM cells. These data suggested that RAD51 might interact noncovalently with SUMO. We found that in vitro RAD51 interacts noncovalently with SUMO and that it interacts more efficiently with SUMO-modified BLM compared to unmodified BLM. These data suggest that SUMOylation controls the switch between BLM's pro- and anti-recombinogenic roles in HR. In the absence of BLM SUMOylation, BLM perturbs RAD51 localization at damaged replication forks and inhibits fork repair by HR. Conversely, BLM SUMOylation relieves its inhibitory effects on HR, and it promotes RAD51 function.
| S-EPMC2779653 | biostudies-literature
Project description:BackgroundProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.MethodsWe analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.ResultsThe most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.ConclusionsThese results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
| S-EPMC9116026 | biostudies-literature
Project description:BackgroundMutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent.MethodsGene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease.ResultsPTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]).ConclusionsPTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.
| S-EPMC8638193 | biostudies-literature