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Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies

¹ Department of Epidemiology and Surveillance Research, American Cancer Society, National Home Office, Atlanta, Georgia; ² Department of Epidemiology and ³ Program in Molecular and Genetic Epidemiology, Harvard School of Public Health; ⁴ Division of Preventive Medicine and ⁵ Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁶ Foundation Jean Dausset, CEPH, Paris, France; ⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland; ⁸ Hormones and Cancer Group and ⁹ Unit of Nutrition and Cancer, IARC, Lyon, France; ¹⁰ Keck School of Medicine and ¹¹ Division of Biostatistics and Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; ¹² Broad Institute at Harvard and Massachusetts Institute of Technology; ¹³ Whitehead Institute for Biomedical Research, Cambridge, Massachusetts; ¹⁴ Department of Medicine, Lund University, Malmö, Sweden; ¹⁵ Epidemiology Unit, National Cancer Institute, Milan, Italy; ¹⁶ Medical Research Council Dunn Nutrition Unit, Cambridge, United Kingdom; ¹⁷ Core Genotyping Facility, National Cancer Institute, Gaithersburg, Maryland; ¹⁸ Institut National de la Sante et de la Recherche Medicale, Institut Gustave Roussy, Villejuif, France; ¹⁹ Cancer Research Center, University of Hawaii, Honolulu, Hawaii; ²⁰ Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany; ²¹ Epidemiology Department, Murcia Health Council, Murcia, Spain; ²² Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands; ²³ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; and ²⁴ Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece

Requests for reprints: Heather Spencer Feigelson, Department of Epidemiology and Surveillance Research, American Cancer Society, 1599 Clifton Road Northeast, Atlanta, GA 30329. Phone: 404-929-6815; Fax: 404-327-6450; E-mail: heather.feigelson{at}cancer.org.

The 17ß-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X² = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study. (Cancer Res 2006; 66(4): 2468-75)

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