BMC Cancer Research article Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes Alice J Sigurdson*1, Michael Hauptmann2, Nilanjan Chatterjee2, Bruce H Alexander3, Michele Morin Doody1, Joni L Rutter4 and Jeffery P Struewing4 BioMed Central Open Access Address: 1Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Boulevard, Bethesda, Maryland, 20892-7238, USA, 2Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Boulevard, Bethesda, Maryland, 20892-7238, USA, 3Division of Environmental and Occupational Health, University of Minnesota, MMC 807 Mayo Building, 420 Delaware Street S.E., Minneapolis, MN, 55455, USA and 4Laboratory of Population Genetics, National Cancer Institute, NIH, DHHS, Building 41, D702, Bethesda, Maryland, 20892-5060, USA Email: Alice J Sigurdson* - sigurdsa@mail.nih.gov; Michael Hauptmann - Hauptmam@mail.nih.gov; Nilanjan Chatterjee - Chattern@mail.nih.gov; Bruce H Alexander - balex@umn.edu; Michele Morin Doody - doodym@mail.nih.gov; Joni L Rutter - rutterj@mail.nih.gov; Jeffery P Struewing - struewij@mail.nih.gov * Corresponding author Published: 12 March 2004 BMC Cancer 2004, 4:9 This article is available from: http://www.biomedcentral.com/1471-2407/4/9 Received: 05 January 2004 Accepted: 12 March 2004 © 2004 Sigurdson et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Breast cancerkin-cohortgenetic variationepidemiologymethodsrisk factors Abstract Background: Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFß1, IGFBP3) were evaluated. Methods: Genomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported. Results: Genotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3–3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1–3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6–29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFß1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P. Page 1 of 12 (page number not for citation purposes)