Analysis of 17β-hydroxysteroid dehydrogenase types 5, 7, and 12 genetic sequence variants in breast cancer cases from French Canadian Families with high risk of breast and ovarian cancer
Analysis of 17β-hydroxysteroid dehydrogenase types 5, 7, and 12 genetic sequence variants in breast cancer cases from French Canadian Families with high risk of breast and ovarian cancer
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DOI：
10.1016/j.jsbmb.2009.05.005
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发表时间：
2009-09-01
影响因子：
4.1
通讯作者：
Simard, Jacques
中科院分区：
文献类型：
--
作者：
Plourde, Marie;Ferland, Alexandra;Simard, Jacques
家族史和雌激素暴露是众所周知的乳腺癌危险因素。17 β-羟基类固醇脱氢酶家族的成员负责外周组织（包括乳腺）中雄激素和雌激素代谢的重要步骤。7 β-HSDs的重要生物学功能使这些基因成为参与乳腺癌病因学的良好候选基因。本研究筛选了编码参与雌二醇生物合成的酶的HSD 17 B7和HSD 17 B12基因以及编码参与雄激素和孕酮代谢的17 β-HSD 5型酶的AKR 1C 3基因的突变，以评估这些基因中的高等位基因变体是否与乳腺癌易感性有关。来自非BRCA 12高风险法裔加拿大家庭的50例乳腺癌病例的突变筛查未能识别HSD 17 B7、HSD 17 B12和AKR 1C 3基因中可能的生殖系高风险突变。然而，鉴定了107个序列变体，包括7个错义变体。错义变体对相应酶的酶活性的影响的评估显示，17 β-HSD 7型和12型的变体与野生型酶之间的催化性质没有差异，而17 β-HSD 5型中的变体p.Glu77Gly和p.Lys183Arg显示出略微降低的活性。最后，一个基于单体型的方法被用来确定标记SNPs提供有价值的信息的研究，调查这些基因中的常见变异与乳腺癌风险的关联。(C)2009爱思唯尔有限公司版权所有。
A family history and estrogen exposure are well-known risk factors for breast cancer. Members of the 17 beta-hydroxysteroid dehydrogenase family are responsible for important steps in the metabolism of androgens and estrogens in peripheral tissues, including the mammary gland. The crucial biological function of 7 beta-HSDs renders these genes good candidates for being involved in breast cancer etiology. This study screened for mutations in HSD17B7 and HSD17B12 genes, which encode enzymes involved in estradiol biosynthesis and in AKR1C3, which codes for 17 beta-HSD type 5 enzyme involved in androgen and progesterone metabolism, to assess whether high penetrance allelic variants in these genes could be involved in breast cancer susceptibility. Mutation screening of 50 breast cancer cases from non-BRCA1/2 high-risk French Canadian families failed to identify germline likely high-risk mutations in HSD17B7, HSD17B12 and AKR1C3 genes. However, 107 sequence variants were identified, including seven missense variants. Assessment of the impact of missense variants on enzymatic activity of the corresponding enzymes revealed no difference in catalytic properties between variants of 17 beta-HSD types 7 and 12 and wild-type enzymes, while variants p.Glu77Gly and p.Lys183Arg in 17 beta-HSD type 5 showed a slightly decreased activity. Finally, a haplotype-based approach was used to determine tagging SNPs providing valuable information for studies investigating associations of common variants in these genes with breast cancer risk. (C) 2009 Elsevier Ltd. All rights reserved.