Mapping Prostate Cancer Susceptibility Genes at 8p22-23

描述(申请人提供)：染色体8p臂上的一个或多个基因与前列腺癌的发生有关，因为在10多年前首次观察到该臂在前列腺癌细胞中频繁缺失。然而，8P上没有确定的前列腺癌基因。最近，我们实验室和其他小组的一系列新观察表明，8P的胚系变异是前列腺癌发生的重要遗传成分，包括：1)多项研究证明遗传性前列腺癌(HPC)家系中8p22-23处存在连锁；2)在HPC患者中观察到涉及8p22-23的胚系重排(倒置、重复)；3)我们团队的最新发现是MSR1(巨噬细胞清道夫受体1)基因与前列腺癌风险相关；4)在没有MSR1突变的家系中，8p22-23区域有额外的前列腺癌基因的证据，因为正连锁仍然存在，并转移到8p22-23区域的端粒一侧。因此，我们假设8p22-23上的额外的胚系序列变异增加了个体对前列腺癌的易感性，并且MSR1是一个主要的前列腺癌易感基因。为了验证这些假说，我们建议使用连锁、测序、基于家族的关联研究和功能研究的组合，在206个至少有3名患有前列腺癌的男性的HPC家庭中进行大规模和独特的收集。我们有以下三个具体目标：1)通过筛选已知和新的MSR1突变，并在新收集的47个MSR1突变家系和11个MSR1突变家系的其他成员中评估其与前列腺癌的共分离，获得MSR1作为主要前列腺癌易感基因的进一步证据。2)对无MSR1突变家系的先证者进行直接测序，以确定8p22-23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测试来评估已识别的突变/序列变异与前列腺癌风险之间的关联。4)通过测量与前列腺癌风险相关的突变/序列变体的子集的mRNA和蛋白质水平的表达，开始评估突变/序列变体的功能变化。前列腺癌基因的成功识别将对理解前列腺癌的病因、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.