Short Communication BRCA1 Susceptibility Markers and Postmenopausal Breast Cancer: The Iowa Women’s Health Study 1 J. A. Thompson, P-L. Chen, R. A. King, S. S. Rich, W. S. Oetting, C. Armstrong, A. R. Folsom, and T. A. Sellers 2 Division of Epidemiology [J. A. T., P-L. C., A. R. F.] and Department of Medicine [R. A. K., W. S. O., C. A.], University of Minnesota; Wake Forest University School of Medicine [S. S. R.]; and Department of Health Sciences Research, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, Minnesota 55905 [T. A. S.] Abstract Much research on early-onset breast cancer families has been performed and has shown that breast cancer in many of these families is linked to either BRCA1 or BRCA2. Fewer studies have examined the role of genetic predisposition in postmenopausal breast cancer. A nested case-control family study of breast cancer was conducted within the Iowa Women’s Health Study, a population-based prospective study of 41,836 postmenopausal women. Probands were 251 incident cases diagnosed between 1988 and 1989. Three-generation pedigrees were developed through mailed questionnaires. From this collection of pedigrees, thirteen were identified for more detailed genetic analysis. Sibling-pair linkage analyses were performed using polymorphic markers in candidate regions in these 13 families with multiple cases of breast and other cancers. Four of the DNA markers are located on chromosome 17, and two of these (D17S579 and THRA1) flank the BRCA1 locus. Significant evidence for linkage to D17S579 was obtained in the total sample, in a model without inclusion of covariates or age at onset (P  0.005), and in a model adjusted for five measured covariates and for variable age at onset (P  0.008). Complete sequencing of the BRCA1 gene in these families, including all intron/exon boundaries, failed to reveal any mutations in 24 women with breast cancer from the 13 families. These data suggest that in some families identified by postmenopausal breast cancer cases, breast cancer risk may be mediated by a gene (or genes) in the BRCA1 region, but not BRCA1 itself. Introduction A family history of breast cancer has been shown to increase a woman’s risk of the disease. For some women, a family history of breast cancer represents inherited susceptibility, which is estimated to be responsible for approximately 5% of all cases (1). This suggests that about 1 in 160 women will develop breast cancer due to an inherited predisposition. Risk increases as age of onset in the affected family member decreases (2– 4), but risk remains elevated in women whose primary relatives were diagnosed with late-onset breast cancer (5–7). In the IWHS, 3 risk to sisters of postmeno- pausal breast cancer cases was increased for both early-onset (relative risk = 1.41) and late-onset (relative risk = 1.81) disease after controlling for measured risk factors (7). Segregation analy- ses have also supported the role of a major gene in late-onset breast cancer (8, 9). Genetic factors may therefore be relevant to late- onset breast cancer development. Much research has been published on genetic factors in early-onset disease. Recently, there has been considerable focus on the BRCA1 locus, a site at which mutation carriers are predisposed to developing breast and ovarian cancers. Estimates of the fre- quency of women carrying BRCA1 mutations range from 1 in 200 to 1 in 2000 (10), and the risk of developing breast cancer by age 70 among carriers has been estimated to be up to 80% (11). Although some of the variation in the occurrence of breast cancer associated with BRCA1 mutations may be due to differences in the mutations [with at least 254 mutations identified to date (12)], variable penetrance suggests that other genetic and environmental factors contribute to the development of the disease. One example is HRAS1 variable number tandem repeats that have been shown to modify the risk of ovarian cancer (but not breast cancer) in BRCA1 mutation carriers (13). Narod et al. (14) also reported on risk modifiers of BRCA1 mutations, including reproductive factors such as age at menarche (below age 12), parity (3), and year of birth (after 1930). These factors could not explain the total varia- bility of expression and penetrance. Beyond the findings of a few reports, it remains uncertain what factors, modifiable or not, may delay or prevent disease onset in BRCA1 mutation carriers. Anthropometric variables (15) and the number of pregnan- cies have also been shown to affect the risk of breast cancer (15–17). We previously showed in this population of women that the increase in risk of breast cancer associated with a high WHR or low parity is more pronounced among women with a family history of breast cancer compared with those without such a family history (17), especially for breast/ovarian cancer (18). These data suggest that genetic factors may be relevant to late-onset breast cancer and that heterogeneity may be influenced by nongenetic risk factors. Mutations in the BRCA1 gene are estimated to account for nearly one-half of early-onset breast cancer families (19). Most of the studies examining the role of BRCA1 have identified Received 4/30/99; revised 2/2/00; accepted 2/28/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported in part by The Margaret Mitchell Scholarship of the American Cancer Society, Minnesota Division and by grants from the National Cancer Institute (R01-CA39742 and R01-CA55747), the American Cancer Society (IN-13-30-14), and the Biomedical Research Support Grant Program, Division of Research Resources (S07-RR55448 and N01-RR00400). Some of the results were obtained using the program package S.A.G.E., which is supported by Grant RR03655 from the Division of Research Resources. 2 To whom requests for reprints should be addressed, at Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905. 3 The abbreviations used are: IWHS, Iowa Women’s Health Study; IBD, identical by descent; BMI, body mass index; WHR, waist:hip ratio. 507 Vol. 9, 507–511, May 2000 Cancer Epidemiology, Biomarkers & Prevention