中国人群前列腺癌低频高外显遗传变异的发现及其功能分析

项目名称： 中国人群前列腺癌低频高外显遗传变异的发现及其功能分析

项目编号： No.81202269

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 预防医学、地方病学、职业病学、放射医学

项目作者： 林晓玲

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 前列腺癌在我国的发病率逐年增长，是常见的泌尿系统肿瘤之一。目前，GWAS研究已经找到了许多与前列腺癌风险相关的常见变异，但这些变异对前列腺癌遗传风险的影响较小（OR<1.3）。我们近期在欧美人群中发现HOXB13基因上的低频高外显遗传变异G84E对前列腺癌风险起到很大作用，其危险性增加10-20倍。同时，我们也在中国人群中发现HOXB13上的低频变异对前列腺癌风险影响很大。这些研究提示：找出前列腺癌风险相关的低频高外显遗传变异可能在一定程度上解决前列腺癌"遗传性缺失"的问题，对于提高前列腺癌的风险评估具有重要意义。我们此次采用大样本病例-对照研究方法，利用课题组前期1000对病例对照样本的Exome芯片扫描信息，筛选出前列腺癌风险相关的低频变异，在中国人群1500对病例对照样本中分两阶段进行验证，并对发现的低频高外显遗传变异进行初步的功能实验分析，为前列腺癌分子机制的研究提供科学。

中文关键词： 前列腺癌；遗传易感性；低频变异；；

英文摘要： Prostate cancer is one of the most common cancers in men. Genome-wide association (GWA) studies have identified over 40 single-nucleotide polymorphisms (SNPs) that are associated with prostate cancer risk. However, these SNPs confer only modest risk to prostate cancer, with odds ratios (OR) &lt; 1.3, and account for less than 25% genetic risk of prostate cancer. To address the 'missing inheritance' of prostate cancer, we recently searched for mutations in 200 genes using a next-generation sequencing method and found that a rare mutation in HOXB13 (G84E) confered a strong risk for prostate cancer in populations of European descent, with OR of 10-20. We also found a novel mutation in HOXB13 (G135E) confered a strong risk to prostate cancer in Chinese men. Based on these findings, we hypothesize that multiple rare and high-penetrant mutations may account for genetic susceptibility to prostate cancer. Built upon a recently completed Exome SNP Array that examinied ~250,000 coding mutations in the genome among 1,000 Chinese prostate cancer cases and 1,000 controls, we propose a two-stage confirmation study among 1,500 Chinese prostate cancer cases and 1,500 controls, to identify rare and high-penetrant prostate cancer risk variants in Chinese. We also propose a functional study to understand moelcular mechanisms of mutat

英文关键词： Prostate cancer；Hereditary susceptibility；Rare variant；；