A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers

Kadouri, Luna; Kóte-Jarai, Zsofia; Hubert, Ayala; Durocher, Francine; Abeliovich, Dvorah; Gläser, Benjamin; Hamburger, Tamar; Eeles, Rosalind; Peretz, Tamar

doi:10.1038/sj.bjc.6601837

Cited by 93 publications

(75 citation statements)

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“…Rare alleles of the oncogene HRAS1 increase risk for ovarian cancer, but not breast cancer, among BRCA1 carriers (11). A polymorphism in the 5Ј UTR of the RAD51 gene (135 G3C, rs1801320) increases risk for breast cancer, but not ovarian cancer, among BRCA2 carriers (12)(13)(14). The magnitude of the RAD51 effect (HR ϭ 3.2-5.5) is consistent with that observed for breast cancer in relatives of breast cancer index cases.…”

Section: Discussionsupporting

confidence: 72%

Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

Simchoni

Friedman

Kaufman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Inherited mutations in BRCA1 and BRCA2 lead to significantly increased risks of breast and ovarian cancer. We used epidemiologic methods to evaluate the relative risks of breast cancer vs. ovarian cancer among women of Ashkenazi Jewish ancestry with inherited mutations in BRCA1 or BRCA2. The cancer of a family's index case (i.e., breast cancer vs. ovarian cancer) was significantly associated with site-specific risks of cancer in relatives known to carry mutations in BRCA1 or BRCA2. Specifically, breast cancer risks were higher among relatives of breast cancer index cases compared with relatives of ovarian cancer index cases [hazard ratio (HR) ‫؍‬ 3.0, P < 0.001 for BRCA1 carriers and HR ‫؍‬ 4.8, P ‫؍‬ 0.017 for BRCA2 carriers], and ovarian cancer risks were higher among relatives of ovarian cancer index cases compared with relatives of breast cancer index cases (HR ‫؍‬ 7.2, P ‫؍‬ 0.001 for BRCA1 carriers and HR ‫؍‬ 15.8, P ‫؍‬ 0.018 for BRCA2 carriers). Breast and ovarian cancer risks also increased with more recent year of birth. For each later decade of birth, risk increased 1.2-fold (P ‫؍‬ 0.03). Effects of cancer site of the index case and of birth cohort were independent. These results suggest that both genetic and nongenetic factors modify cancer risks among BRCA1 and BRCA2 mutation carriers, and that genetic modifiers and other familial factors may influence risk specifically for either breast or ovarian cancer.breast cancer ͉ ovarian cancer ͉ penetrance ͉ hereditary cancer I n the decade since BRCA1 (MIM 113705) and BRCA2 (MIM 600185) were identified as susceptibility genes for breast and ovarian cancer, testing of these genes has become part of clinical practice, and thousands of women worldwide have been identified as carriers of mutations in BRCA1 or BRCA2. Women with cancer-predisposing mutations are offered intensive surveillance for early cancer detection and͞or preventive measures. Although prevention of breast and ovarian cancer in carriers is highly effective, it primarily involves prophylactic surgery: oophorectomy and risk-reduction mastectomy (refs. 1 and 2 and reviewed in ref.3). In considering the best course of action for mutation carriers, it is essential to have accurate estimates of possible outcomes that include all genetic and nongenetic factors influencing risk.Breast cancer risks associated with BRCA1 and BRCA2, and ovarian cancer risk associated with BRCA1, have been shown to be higher in more recent birth cohorts (4-6). These secular (time) trends likely reflect nongenetic influences because risk changed within families among individuals with the same mutations. Meta-analysis further suggested that cancer risk among BRCA1 and BRCA2 carriers was influenced by the site of cancer (i.e., breast cancer or ovarian cancer) in the index case (5). This observation suggested that genetic modifiers, alleles of genes other than BRCA1 or BRCA2, might affect outcome in carriers of BRCA1 or BRCA2 mutations.The goal of this study was to investigate the influences of cancer site in the index case ...

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Section: Discussionsupporting

confidence: 72%

Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

Simchoni

Friedman

Kaufman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Since distributions of age and disease status were different in the Ashkenazi and nonAshkenazi populations, the analyses were adjusted for ethnic origin. Although selection of participants is partly based on outcome, this method of analysis was used previously for risk estimation in carriers (Rebbeck et al, 1999;Levy-Lahad et al, 2001;Kadouri et al, 2004a). In our study (Kadouri et al, 2001) on the modifying effect of the androgen receptor-CAG-repeat length in BRCA carriers, we compared COX proportional hazard models to a variant of the log rank designed to overcome selection bias by comparison of outcome to expected penetrance according to the literature.…”

Section: Discussionmentioning

confidence: 99%

“…The study population has been reported previously (Kadouri et al, 2004a). In summary, blood samples from 320 BRCA1/2 carriers were collected through two centres: 240 carriers were identified by the oncology department and the cancer genetic clinic in the Hadassah Medical Centre in Jerusalem, Israel, and 80 at the cancer genetic carrier clinic in the Royal Marsden NHS Foundation Trust, London, UK.…”

Section: Study Populationmentioning

confidence: 99%

Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers

et al. 2008

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5The Royal Marsden NHS Foundation Trust, Sutton, UK Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65 -1.12, P ¼ 0.25) and 1.11 (95% CI 0.81 -1.52, P ¼ 0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02 -1.81, P ¼ 0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18 -3.38) for carriers of the Val/Val genotype (P ¼ 0.01). An HR of 3.20 (95% CI 1.26 -8.09, P ¼ 0.01), and younger age at BC onset (P ¼ 0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1-and GSTT1-null allele did not seem to have a major effect.

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“…63 An SNP 135G4C (RAD51: c.À98G4C) in RAD51 has recently been identified as first modifier in BRCA2 mutation carriers, whereas no effect of this SNP was found in BRCA1 mutation carriers and BRCA1/BRCA2 mutation non-carriers. 64,65 A multicentre study, investigating 10 358 mutation carriers, described modifier roles for SNPs in FGFR2, MAP3K1 and TOX3 that were initially identified as low-penetrance breast cancer susceptibility SNPs. 43 Importantly, the SNPs rs2981582 and rs889312 in FGFR2 and MAP3K1, respectively, increase the breast cancer risk in BRCA2 mutation carriers but not in BRCA1 mutation carriers, whereas rs3803662, an SNP in TOX3, is associated with an increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers.…”

Section: Common Low-penetrance Breast Cancer Susceptibility Snpsmentioning

confidence: 99%

Breast cancer susceptibility: current knowledge and implications for genetic counselling

et al. 2008

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Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.

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A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers

Cited by 93 publications

References 14 publications

Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers

Breast cancer susceptibility: current knowledge and implications for genetic counselling

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