Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers.

Unit of Genetic Epidemiology, IARC, 150, cours Albert-Thomas, 69372 Lyon cedex 08, France.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 02/2005; 14(1):265-7.
Source: PubMed

ABSTRACT The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Hormones are implicated in various types of cancer, however, several aspects of steroid activity on carcinogenesis remain elusive. Recent progress has made it possible for us to directly study the biological mechanisms of disease development, including hormone-cancer relationships, from numerous viewpoints, from numerous viewpoints, including genome abnormalities. One tool is comparative genomic hybridization array (aCGH). Furthermore, it is possible to identify the so-called "cancer signature" by gene expression profiling, which provides new information about the role of steroids on carcinogenesis. DNA mutations and gene expression abnormalities may be associated with hormone-related cancer. The recent discovery of microRNA provides new opportunities for understanding the fine regulation of gene expression in cancer cells, and the role of microRNA in the relationship between hormones and cancer. From these experimental models we should be able to rapidly develop translation-to-treatment protocols. The final goal should be to design specific labs on a microchip for prognosis and therapy of individual patients. While in clinical research there is renewed attention to stratification of patients, especially those at high risk.
    Annals of the New York Academy of Sciences 03/2009; 1155(1):1-3. DOI:10.1111/j.1749-6632.2008.03680.x · 4.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Germline mutations of the BRCA1 and BRCA2 genes confer a high life-time risk of ovarian cancer. They represent the most significant and well characterised genetic risk factors so far identified for the disease. The frequency with which BRCA1/2 mutations occur in families containing multiple cases of ovarian cancer or breast and ovarian cancer, and in population-based ovarian cancer series varies geographically and between different ethnic groups. There are differences in the frequency of common mutations and in the presence of specific founder mutations in different populations. BRCA1 and BRCA2 are responsible for half of all families containing two or more ovarian cancer cases. In population-based studies, BRCA1 and BRCA2 mutations are present in 5-15% of all ovarian cancer cases. Often, individuals in which mutations are identified in unselected cases have no family history of either ovarian or breast cancer. The ability to identify BRCA1/2 mutations has been one of the few major success stories over the last few years in the clinical management of ovarian cancer. Currently, unaffected individuals can be screened for mutations if they have a family history of the disease. If a mutation is identified in the family, and if an individual is found be a mutation carrier, they can be offered clinical intervention strategies that can dramatically reduce their ovarian cancer risks. In some populations with frequent founder mutations screening may not be dependent on whether a mutation is identified in an affected relative.
    Molecular oncology 05/2009; 3(2):138-50. DOI:10.1016/j.molonc.2009.02.001 · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous contralateral breast cancer (CBC, cases) and 1,221 women with unilateral breast cancer (UBC, controls) from the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study. BRCA1 and BRCA2 deleterious mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing, yielding including 88 BRCA1 and 60 BRCA2 deleterious mutation carriers. We also genotyped samples on the Illumina Omni1-Quad platform. We assessed the association between CBC risk and common (minor allele frequency (MAF) > 0.05) single-nucleotide polymorphisms (SNPs) in BRCA1 (n SNPs = 22) and BRCA2 (n SNPs = 30) and haplotypes using conditional logistic regression accounting for BRCA1/BRCA2 mutation status. We found no significant associations between any single-SNPs or haplotypes of BRCA1 or BRCA2 and risk of CBC among all women. When we stratified by BRCA1 and BRCA2 mutation carrier status, we found suggestive evidence that risk estimates for selected SNPs in BRCA1 (rs8176318, rs1060915, and rs16940) and BRCA2 (rs11571686, rs206115, and rs206117) may differ in non-carriers and carriers of deleterious mutations in BRCA1 and BRCA2. One common haplotype on BRCA1 was inversely significantly associated with risk only among non-BRCA1 and BRCA2 carriers. The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status.
    Breast Cancer Research and Treatment 12/2010; 127(3):819-29. DOI:10.1007/s10549-010-1285-1 · 4.20 Impact Factor