Characterization of HSD17B1 sequence variants in breast cancer cases from French Canadian families with high risk of breast and ovarian cancer.

A family history of disease and estrogen exposure are risk factors for breast cancer. The HSD17B1 gene encodes a key steroidogenic enzyme that catalyses the final step of estradiol biosynthesis, rendering it a good candidate gene for breast cancer susceptibility. The current study was designed to screen for HSD17B1 germline mutations potentially involved in breast cancer susceptibility. DNA samples from 50 individuals affected with breast cancer from non-BRCA1/2 French Canadian families with a high risk of breast and ovarian cancer were screened for sequence variants in HSD17B1. Our study identified 28 sequence variants, including three non-synonymous variants, p.Ala238Val, p.Arg259His, p.Ser313Gly, one of which (p.Arg259His) was not previously reported. Functional assays failed to show changes in either activity or recombinant proteins levels for all three variants. Thus, our resequencing analysis does not support the existence of deleterious, gain-of-function or transcription mutations in HSD17B1, which could explain the clustering of breast cancer cases in non-BRCA1/2 high-risk French Canadian families. However, a haplotype-based approach was used to establish tSNPs, providing a valuable tool for further searches of common disease-associated variants in this gene, using large cohorts.