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Mutation and association analysis of GEN1 in breast cancer susceptibility.

ABSTRACT: GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case-control association analyses, to evaluate the contribution of genes to cancer susceptibility.

SUBMITTER: Turnbull C

PROVIDER: S-EPMC3632835 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Mutation and association analysis of GEN1 in breast cancer susceptibility.

Turnbull Clare C Hines Sarah S Renwick Anthony A Hughes Deborah D Pernet David D Elliott Anna A Seal Sheila S Warren-Perry Margaret M Gareth Evans D D Eccles Diana D Stratton Michael R MR Rahman Nazneen N

Breast cancer research and treatment 20100530 1

GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 com ...[more]

PMID: 20512659

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Project description:Genome-wide association studies have reported nearly 100 common germline susceptibility loci associated with the risk for breast cancer. Tumour sequencing studies have characterised somatic mutation profiles in breast cancer patients. The relationship between breast cancer susceptibility loci and somatic mutation patterns in breast cancer remains largely unexplored.We used single-nucleotide polymorphism (SNP) genotyping array data and tumour exome sequencing data available from 638 breast cancer patients of European ancestry from The Cancer Genome Atlas (TCGA) project. We analysed both genotype data and, when necessary, imputed genotypes for 90 known breast cancer susceptibility loci. We performed linear regression models to investigate possible associations between germline risk variants with total somatic mutation count (TSMC), as well as specific mutation types. We examined individual SNP genotypes, as well as a multi-SNP polygenic risk score (PRS). Models were statistically adjusted for age at diagnosis, stage, oestrogen-receptor (ER) and progesterone-receptor (PR) status of breast cancer. We also performed stratified analyses by ER and PR status.We observed a significant inverse association (P=8.75 × 10(-6); FDR=0.001) between the risk allele in rs2588809 of the gene RAD51B and TSMC across all breast cancer patients, for both ER(+) and ER(-) tumours. This association was also evident for different types of mutations. The PRS analysis for all patients, with or without rs2588809, showed a significant inverse association (P=0.01 and 0.04, respectively) with TSMC. This inverse association was significant in ER(+) patients with the ER(+)-specific PRS (P=0.02), but not among ER(-) patients for the ER(-)-specific PRS (P=0.39).We observed an inverse association between common germline risk variants and TSMC, which, if confirmed, could provide new insights into how germline variation informs our understanding of somatic mutation patterns in breast cancer.

Project description:Estrogen has played an important role in the development of breast cancer. ER-? PvuII gene polymorphism is in close association with the occurrence risk of breast cancer, but no consensus has been achieved currently.PubMed, Embase, China National Knowledge Infrastructure (CNKI) database, Wanfang database, and VIP database were retrieved to collect the case-control studies on association between ER? gene Pvu II polymorphism and breast cancer risk published before September 1, 2017. Newcastle-Ottawa Scale (NOS) was used to assess the quality of the literatures, Stata 14.0 software was applied for meta-analysis, and the pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated. The subgroup analysis was performed to assess the confounding factors, followed by assessment of publication bias and sensitivity analysis.A total of 26 studies were enrolled in the analysis based on inclusion criteria, which included 15,360 patients and 26,423 controls. The results demonstrated that ER? gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in 3 genetic models (C vs T, OR?=?0.962, 95% CI?=?0.933-0.992, P?=?.012; CC vs TT, OR?=?0.911, 95% CI?=?0.856-0.969, P?=?.003; CC vs TT/CT, OR?=?0.923, 95% CI?=?0.874-0.975, P?=?.004). Subgroup analysis was conducted on the basis of ethnicity and source of controls, whose results illustrated that ER? gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in Asians rather than in Caucasians (CC vs TT, OR?=?0.862, 95% CI?=?0.750-0.922, P?=?.038; CC vs TT/CT, OR?=?0.851, 95% CI?=?0.755-0.959, P?=?.008). In population-based subgroup rather than in hospital-based subgroup, ER? gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in the allele model, homozygous model, dominant model, and recessive model (C vs T, OR?=?0.943, 95% CI?=?0.911-0.977, P?=?.001; CC vs TT, OR?=?0.878, 95% CI?=?0.817-0.944, P?=?.000; CC/CT vs TT, OR?=?0.936, 95% CI?=?0.881-0.994, P?=?.031; CC vs TT/CT, OR?=?0.902, 95% CI?=?0.847-0.960, P?=?.001).ER? gene Pvu II polymorphism exerts an important function in the progression of breast cancer.

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Mutation and association analysis of GEN1 in breast cancer susceptibility.

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Mutation and association analysis of GEN1 in breast cancer susceptibility.

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