Plourde Marie, Samson Carolle, Durocher Francine, Sinilnokova Olga, Simard Jacques
Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec and Laval University, Quebec G1V 4G2, Canada.
J Steroid Biochem Mol Biol. 2008 Mar;109(1-2):115-28. doi: 10.1016/j.jsbmb.2007.10.004. Epub 2007 Nov 17.
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.
疾病家族史和雌激素暴露是乳腺癌的风险因素。HSD17B1基因编码一种关键的类固醇生成酶，催化雌二醇生物合成的最后一步，使其成为乳腺癌易感性的良好候选基因。本研究旨在筛选可能与乳腺癌易感性相关的HSD17B1种系突变。对来自非BRCA1/2法裔加拿大家庭且患乳腺癌和卵巢癌风险较高的50例乳腺癌患者的DNA样本进行HSD17B1序列变异筛查。我们的研究鉴定出28个序列变异，包括三个非同义变异，即p.Ala238Val、p.Arg259His、p.Ser313Gly，其中一个（p.Arg259His）此前未见报道。功能分析未显示这三个变异的活性或重组蛋白水平有变化。因此，我们的重测序分析不支持HSD17B1中存在有害、功能获得或转录突变，而这些突变可能解释非BRCA1/2高风险法裔加拿大家庭中乳腺癌病例的聚集现象。然而，基于单倍型的方法被用于建立标签单核苷酸多态性，为使用大型队列进一步搜索该基因中常见的疾病相关变异提供了一个有价值的工具。
