Mapping Prostate Cancer Susceptibility Genes at 8p22-23

描述（由申请人提供）：染色体臂8 p上的一个或多个基因与前列腺癌发生有关，因为10多年前描述了前列腺癌细胞中该臂频繁缺失的原始观察结果。然而，在8 p上没有确定的前列腺癌基因。近年来，本实验室和其他研究小组的一系列新观察结果表明，8 p的生殖系变异是前列腺癌发生的重要遗传组成部分，包括：1）多项研究证实8 p22 -23与遗传性前列腺癌（HPC）家系存在连锁关系; 2）生殖系重排的观察（倒置，重复）涉及HPC患者的8 p22 -23; 3）我们组的最新发现，（巨噬细胞清道夫受体1）基因与前列腺癌风险相关;和4）在没有MSR 1突变的家族中，在8 p22 - 23处存在额外的前列腺癌基因的证据，因为阳性连锁仍然存在并转移到8 p22 -23区域的端粒侧。因此，我们假设8 p22 -23基因中额外的种系序列变异增加了个体对前列腺癌的易感性，以及MSR 1是主要的前列腺癌易感基因。为了验证这些假设，我们建议使用连锁，测序，以家庭为基础的关联研究，并在一个大的和独特的收集206 HPC家庭至少有三名男子患有前列腺癌的功能研究的组合。我们有以下三个具体的目标：1）通过筛选已知和新的MSR 1突变，并评估其与前列腺癌的共分离，在47个新收集的家庭和额外的家庭成员的11个家庭MSR 1突变，获得进一步的证据，MSR 1作为一个主要的前列腺癌易感基因。2)在没有MSR 1突变的家族先证者中，使用直接测序法鉴定8 p22 -23连锁区四聚体侧其他基因的突变/序列变异。3)通过进行基于家族的关联性检验，评估已识别的突变/序列变异与前列腺癌风险之间的关联性。4)开始通过测量与前列腺癌风险相关的突变/序列变体子集的mRNA表达和蛋白质水平来评价突变/序列变体的功能变化。成功鉴定前列腺癌基因将对了解前列腺癌的病因、预防、诊断和治疗产生重大影响。

DESCRIPTION (provided by applicant): A gene or genes on chromosome arm 8p have been implicated in prostate carcinogenesis since the original observation of frequent deletions of this arm in prostate cancer cells was described over 10 years ago. However, no definitive prostate cancer gene on 8p has been identified. Recently, a series of new observations from our laboratory and other groups implicate germ line variations of 8p as an important genetic component of prostate carcino genesis, including: 1) demonstration of linkage at 8p22-23 in families with hereditary prostate cancer (HPC) in multiple studies; 2) observation of germ line rearrangements (inversions, duplications) involving 8p22-23 in HPC patients; 3) the most recent finding by our group that the MSR1 (macrophage scavenger receptor 1) gene is associated with prostate cancer risk; and 4) evidence for additional prostate cancer genes at 8p22-23 as positive linkage remains and shifts to the telomeric side of the 8p22-23 region in families without MSR1 mutations. We therefore hypothesize that additional germline sequence variants in genes on 8p22-23 increase individual susceptibility to prostate cancer, as well as that MSR1 is a major prostate cancer susceptibility gene. To test these hypotheses, we propose to use a combination of linkage, sequencing, family-based association studies, and functional studies in a large and unique collection of 206 HPC families with at least three men with prostate cancer. We have the following three specific aims: 1) Obtain further evidence for MSR1 as a major prostate cancer susceptibility gene by screening for known and novel MSR1 mutations and assessing their co-segregation with prostate cancer in the 47 newly collected families and additional family members of the 11 families with MSR1 mutations. 2) Identify mutations/sequence variants in other genes at the tetomeric side of the 8p22-23 linkage region using direct sequencing in probands of the families without MSR1 mutations. 3) Assess the association between the identified mutations/sequence variants and prostate cancer risk by performing family-based association tests. 4) Begin to evaluate the functional changes of the mutations/sequence variants by measuring the expression of mRNA and protein levels for a subset of mutations/sequence variants that are associated with prostate cancer risk. Successful identification of prostate cancer genes will have a significant impact on understanding the etiology, prevention, diagnosis, and treatment of prostate cancer.