Article

DNA repair gene ERCC2 polymorphisms and associations with breast and ovarian cancer risk.

Département d'Oncogénétique du Centre Jean Perrin, EA 2416 CBRV, 28 Place Henri Dunant, B,P, 38, 63001 Clermont-Ferrand Cedex 01, France.
Molecular Cancer (Impact Factor: 5.13). 01/2008; 7:36. DOI: 10.1186/1476-4598-7-36
Source: PubMed

ABSTRACT Breast and ovarian cancers increased in the last decades. Except rare cases with a genetic predisposition and high penetrance, these pathologies are viewed as a polygenic disease. In this concept, association studies look for genetic variations such as polymorphisms in low penetrance genes, i.e. genes in interaction with environmental factors. DNA repair systems that protect the genome from deleterious endogenous and exogenous damages have been shown to have significantly reduced. In particular, enzymes of the nucleotide excision repair pathway are suspected to be implicated in cancer. In this study, 2 functional polymorphisms in a DNA repair gene ERCC2 were analyzed. The population included 911 breast cancer cases, 51 ovarian cancer cases and 1000 controls. The genotyping of 2 SNP (Single Nucleotide Polymorphism) was carried out on the population with the MGB (Minor Groove Binder) probe technique which consists of the use of the allelic discrimination with the Taqman method. This study enabled us to show an increase in risk of breast cancer with no oral contraceptive users and with women exhibiting a waist-to-hip ratio (WHR) > 0.85 for Asn homozygous for ERCC2 312.

0 Bookmarks
 · 
114 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Ovarian cancer is a highly lethal disease. Many researchers have, therefore, attempted to identify high risk populations. In this perspective, numerous genetic association studies have been performed to discover common ovarian cancer susceptibility variants. Accordingly, there is an increasing need to synthesize the evidence in order to identify true associations. A comprehensive and systematic assessment of all available data on genetic susceptibility to sporadic ovarian cancer was carried out. The evidence of statistically significant findings was evaluated based on the number of positive replications, the ratio of positive and negative studies, and the false-positive report probability (FPRP). The authors reviewed three genome-wide association studies (GWAS) and 147 candidate gene studies, published from 1990 to October 2010, including around 1100 genetic variants in more than 200 candidate genes and 20 intergenic regions. Genetic variants with the strongest evidence for an association with ovarian cancer include the rs2854344 in the RB1 gene and SNPs on chromosomes 9p22.2, 8q24, 2q31, and 19p13. Promising genetic pathways for ovarian cancer include the cell cycle, DNA repair, sex steroid hormone and oncogenic pathway. Concluding, this review shows that many genetic association studies have been performed, but only a few genetic variants show strong evidence for an association with ovarian cancer. More research is needed to elucidate causal genetic variants, taking into consideration gene–gene and gene–environment interactions, combined effects of common and rare variants, and differences between histological subtypes of this cancer.
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 12/2011; 1816(2):132. · 9.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetics, particularly DNA methylation, has recently been shown to be important in breast cancer initiation. We investigated the clinical and prognostic importance of whole blood breast cancer early onset gene 1 (BRCA1) DNA methylation in sporadic breast cancer. Genomic DNA was extracted from the peripheral blood cells (PBCs) of 902 breast cancer patients at diagnosis, with no BRCA1 mutation, and 990 control women. DNA methylation was measured by quantitative analysis of methylated alleles (QAMA) to estimate the extent of methylation of 2 CpG sites in the promoter region of BRCA1 oncosuppressor. BRCA1 promoter methylation rate in PBCs was 47.1% with a 95% confidence interval [46.1; 48.1] in breast cancer patients, and 45.9% with a 95% confidence interval [45.0; 46.8] in controls. We found a trend toward BRCA1 promoter hypermethylation in PBCs of sporadic breast cancer patients compared with controls. Association between methylation and clinicopathological features was evaluated using statistical tests. BRCA1 promoter methylation in PBCs increased significantly in breast cancer patients compared with controls, for age over 70 years (p=0.022), in post-menopausal status (p=0.013), for a body mass index (BMI) <20 (p=0.0095) or a waist-to-hip ratio (WHR) ≤76.8 (p=0.0027). We also found an association of increased BRCA1 promoter methylation in PBCs with ACA/ACA genotype for the SNP Thr594Thr in ESR (estrogen receptor gene), known to be associated with breast cancer risk (p=0.092), reflecting the reduced presence of this genotype in this breast cancer case-control study. Analysis of site-specific DNA methylation in PBCs by QAMA provides quantitative DNA methylation values that may serve as important prognostic indicators.
    Cancer epidemiology. 03/2012; 36(3):e177-82.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different cancer diseases. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40 % of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. The aim of the present study was to evaluate the role of SNPs in three genes, XRCC2 (R188H), ERCC2 (K751Q) and CDKN1B (V109G) which are with moderate risk for ovarian cancer susceptibility in Egyptian women. We further investigated the potential combined effect of these genes variants on ovarian cancer risk. The three genes polymorphisms were characterized in 100 ovarian cancer Egyptian females and 100 healthy women by (RFLP-PCR) method in a case control study. Our results revealed that the frequencies of AC genotypes of ERCC2 (K751Q), and GG genotypes of CDKN1B (V109G) polymorphisms were significantly higher in EOC patients than in normal individual (P = 0.007, 0.02 respectively). The frequencies of AA genotype of XRCC2 (R188H) and CC genotype of ERCC2 (K751Q) were higher in EOC patients than in normal individual but without significance (P = 0.06, 0.38 respectively). Also, no association between any one of the three studied genes polymorphisms and the clinical characteristics of disease. The combination of GA (XRCC2) + AC (ERCC2) + GG (CDKN1B) was significantly associated with increased EOC risk. Also, the combination for GA (XRCC2) + AC (ERCC2) and the combination of AA (XRCC2) + CC (ERCC2) were significantly associated with increased EOC risk. There was significant difference in CA125 values between EOC and control Group (P < 0.001). Our results suggested that, XRCC2, ERCC2 and CDKN1B genes are important candidate genes for susceptibility to EOC. Also, gene-gene interaction between GA (XRCC2) + AC (ERCC2) + GG (CDKN1B) polymorphism may be associated with increased risk of EOCC in Egyptian women.
    Molecular Biology Reports 01/2013; · 2.51 Impact Factor

Full-text (2 Sources)

View
30 Downloads
Available from
May 22, 2014