The 17 beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis, namely the conversion of estrone to the more biologically active estradiol. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. We report here the results from a large, International collaborative study, the NCI Breast and Prostate Cancer Cohort Consortium (BPC3), of breast cancer and HSD17B1. The study includes 3,800 cases of European and U.S. whites and 6,000 matched controls drawn from 5 large, well-established cohorts. We conducted a comprehensive analysis of the genomic region of HSD17B1, including SNP discovery, haplotype construction, and selection of haplotype-tagging SNPs (htSNPs). Twenty-six validated SNPs located within a 42 kb genomic region in and around HSD17B1 were selected for haplotype determination by (1) sequencing germline DNA from 95 patients with advanced breast cancer from a multiethnic cohort (MEC) and (2) searching a public database for common markers located, on average, every 2kb in the gene region starting 30 kb upstream of the transcription start codon, across the gene and 10 kb downstream of the last exon. The 26 SNPs were genotyped in 349 women without a history of cancer drawn from the MEC, and htSNPs were chosen using the method of Stram et al (2003). This method infers haplotype frequencies and maximizes a measure of correlation, RSQ-H, between the genotypes of the htSNPs and the haplotypes themselves. The cumulative frequency of the three most common haplotypes among the European-US population of the MEC was 83%. Three htSNPs, as well as a previously studied SNP, +2923A/G (S312G), were selected for the European-US population and genotyped in cases and controls. The RSQ-H statistic for these htSNPs was 0.82. Among the controls, the cumulative frequency of the three common haplotypes was 93%. The odds ratios (OR) for each haplotype relative to the most common haplotype ranged from 1.00 to 1.07, global p for heterogeneity=0.79. The ORs for the +2923A/G SNP hypothesized to alter the function of HSD17B1 were A/G:0.98 (95%CI: 0.89-1.08) and G/G:0.96 (95%CI: 0.85-1.08) compared to the A/A genotype. This analysis provides no evidence that genetic variation in HSD17B1 is associated with breast cancer risk as a main effect among white women of European decent. Analyses are currently underway to assess whether the associations differ among subgroups defined by exposure and demographic variables.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]