Null Results in Brief The Role of Established Breast Cancer Susceptibility Loci in Mammographic Density in Young Women Eunjung Lee, 1 Christopher A. Haiman, 1 Huiyan Ma, 2 David Van Den Berg, 1 Leslie Bernstein, 1,3 and Giske Ursin 1,4 1 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC/Norris Comprehensive Cancer Center, Los Angeles, California; 2 Institute for Health Promotion and Disease Prevention Research, Keck School of Medicine, University of Southern California, Alhambra, California; 3 City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, California; and 4 Department of Nutrition, University of Oslo, Oslo, Norway Introduction Recently, three genome-wide association studies identi- fied and validated multiple novel loci as contributors to breast cancer susceptibility (1-3). In two of these studies (1, 2), the most significant association was with a common variant (rs2981582) in FGFR2 , a gene implicat- ed in mammary carcinogenesis (4-6). However, for all loci, the specific biological pathways that are disrupted and the mechanisms through which these common genetic variations contribute to breast cancer risk remain unclear. Mammographic density (MD) is an important risk factor for breast cancer (7) and might be predominantly inherited (8), but the gene(s) responsible are, to a large extent, unknown. In the present study, we investigated whether these established breast cancer variants are also associated with MD. Given the known effects of postme- nopausal hormone therapy on MD (9, 10), we addressed this question in a study of breast cancer patients under theageof50. Materials and Methods This study has previously been described (11). Female patients diagnosed with histologically confirmed first primary invasive breast cancer were identified through the Los Angeles County Cancer Surveillance Program. EligiblecaseswereU.S.-bornandEnglishspeaking,white (including Hispanic) or African-American females, ages 20to49years.Amongthe2,882potentiallyeligiblecases, 1,794 (62%) were interviewed. The study was approved by the Institutional Review Board of the University of Southern California. All participants provided written informedconsent. All subjects were interviewed in-person using a structured questionnaire which covered information on standard breast cancer risk factors. We obtained and digitized mammographic films of the contralateral (non- cancerous) breast on 639 of 866 women with unilateral cancer for whom we requested mammograms. Estrogen and progesterone receptor information (ER/PR) was abstracted from pathology reports. Bloodspecimenswerecollectedfrom588(92%)women with mammograms. DNA was available on 578 women forthecurrentstudy.Theheterogeneityofgeneticeffects has been observed for some of these variants between African-Americans and other populations, which pre- sumably reflects differences in linkage disequilibrium between these variants and the underlying causal alleles (1, 3). Thus, we limited our analysis to 516 whites (429 non-Hispanic, 87 Hispanic). We genotyped six single nucleotide polymorphisms (SNP; rs889312, rs2981582, rs3803662, rs3817198, rs13281615, and rs13387042) using TaqMan assays as previously described (1, 3). The genotyping call rate was 97% to 98% for all six SNPs. We included 33 blind duplicate samples which had completely consistent results with the original samples. All SNPs were in Hardy-Weinberg equilibrium in each population. MD was quantified (by G. Ursin) using the University of Southern California Madena computer-assisted assess- ment method (12). The breast area was outlined by a research assistant trained by G. Ursin. The Madena soft- warecountstheareaofabsolutedensityaswellasthetotal breast area. The percent mammographic density was equivalent to the amount of absolute density divided by thetotalbreastarea. Statistical Analyses. We examined the association between the carrier status of these SNPs and the mammographic percentage density using multivariable linear regression. The models were adjusted for age at diagnosis,ethnicity,menopause,hormoneuse,andbody mass index 1 year prior to the diagnosis. We examined allele dosage effects because the previous studies Cancer Epidemiol Biomarkers Prev 2008;17(1). January 2008 Cancer Epidemiol Biomarkers Prev 2008;17(1):258–60 Received 11/2/07; accepted 11/2/07. Grant support: CA17054 and CA74847 from the National Cancer Institute, NIH, 4PB-0092 from the California Breast Cancer Research Program of the University of California, and in part through NIH contract no. N01-PC-35139. The collection of cancer incidence data used in this publication was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ideas and opinions expressed herein are those of the authors, and no endorsement by the State of California, Department of Health Services is intended or should be inferred. 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. Requests for reprints: Giske Ursin, Department of Preventive Medicine, Keck School ofMedicine,UniversityofSouthernCalifornia/NorrisComprehensiveCancerCenter, Room 4407, 1441 Eastlake Avenue, Los Angeles, CA 90089. Phone: 323-865-0423; Fax: 323-865-0142. E-mail: gursin@usc.edu Copyright D 2008 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-07-2749 258 Research. on October 7, 2021. © 2008 American Association for Cancer cebp.aacrjournals.org Downloaded from