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Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Implications for risk prediction
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2010 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed) Published
Abstract [en]

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10-11 - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Place, publisher, year, edition, pages
American Association for Cancer Research , 2010. Vol. 70, no 23, p. 9742-9754
Keywords [en]
BRCA1 protein, BRCA2 protein, adult, aged, article, attributable risk, breast cancer, cancer risk, cancer susceptibility, clinical evaluation, controlled study, female, follow up, gene frequency, gene mutation, genotype, heterozygote, human, major clinical study, priority journal, probability, risk assessment, single nucleotide polymorphism, tumor suppressor gene, Aged, 80 and over, Alleles, Breast Neoplasms, Genetic Predisposition to Disease, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Receptors, Progesterone, Risk Factors, Sodium-Bicarbonate Symporters, Survival Analysis, Vesicular Transport Proteins
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:hj:diva-39678DOI: 10.1158/0008-5472.CAN-10-1907ISI: 000285045900024PubMedID: 21118973Scopus ID: 2-s2.0-78649980806OAI: oai:DiVA.org:hj-39678DiVA, id: diva2:1212093
Note

SWE-BRCA

SWE-BRCA collaborators: Per Karlsson, Margareta Nordling, Annika Bergman, and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Sigrun Liedgren, Linkoping University Hospital; Niklas Loman, Ha kan Olsson, Ulf Kristoffersson, Helena Jernstr€om, Katja Harbst, and Karin Henriksson, Lund University Hospital; Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, and Gisela Barbany-Bustinza, Stockholm, Karolinska University Hospital; Henrik Gronberg, Eva-Lena Stattin, and Monica Emanuelsson, Umea University Hos- € pital; Hans Ehrencrona, Richard Rosenquist Brandell, and Niklas Dahl, Uppsala University Hospital

Available from: 2018-06-01 Created: 2018-06-01 Last updated: 2018-06-01Bibliographically approved

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