P-2: Genetic and Clinical Characterization of the 8q24 Prostate Cancer Risk Locus

前列腺癌的遗传因素前列腺癌的风险已被证明难以识别。的结果 连锁分析是孟德尔遗传病基因发现方法的主力， 难以验证。然而，在过去的一年里，两项独立的研究表明， 8q24上的基因突变赋予非洲和欧洲男性患散发性前列腺癌的强烈风险， 祖先8q24是第一个真正的遗传风险位点，它负责相当一部分的 散发性前列腺癌病例在一般人群中，特别是在非洲裔美国男性中。我们 假设8q24内的遗传变异引发前列腺癌并影响临床特征 疾病。 这个新基因座的发现为深入了解前列腺癌生物学提供了机会。 虽然该区域已经确定，但致病等位基因及其影响的基因仍然是未知的。 测定由于8q是前列腺癌中体细胞扩增最频繁的区域之一，我们将 也有机会探索生殖细胞和体细胞基因组之间的联系。 了解驱动前列腺癌的遗传和分子途径最终可以改善 诊断和治疗能力。从临床角度来看，患者可以分为携带者和 非该风险等位基因携带者，以探讨其对临床变量的影响，如表现和疾病 结果。我们的目标是阐明8q24变异的遗传发病机制和临床影响。 前列腺癌的等位基因 该项目的具体目标是： 目的1：通过8q24区域的精细定位来识别致病种系等位基因 目的2：研究8q24的遗传变异和8q24的体细胞分子关联 目的3：确定生殖系8q24变异体对临床表现和预后的影响， 前列腺癌患者

Inherited factors for prostate cancer prostate cancer risk have proven difficult to identify. The results of linkage analysis, the workhorse of gene finding methods for Mendelian disorders, have been notoriously difficult to validate. Within the past year, however, two independent studies have demonstrated that a region on 8q24 confers a strong risk of developing sporadic prostate cancer in men of African and European ancestries. 8q24 is the first bona fide genetic risk locus that is responsible for an appreciable fraction of sporadic prostate cancer cases in the general population, particularly, in African-American men. Our hypotheses are that a genetic variant within 8q24 initiates prostate cancer and impacts the clinical features of the disease. The discovery of this novel locus presents the opportunity to gain deeper insight into prostate cancer biology. Although the region has been identified, the causal allele and the gene that it influences remain to be determined. Since 8q is one of the most frequent regions of somatic amplification in prostate cancer, we will also have the opportunity to explore connections between the germline and somatic genomes. Understanding the genetic and molecular pathways driving prostate cancer can ultimately lead to improved diagnostic and therapeutic capabilities. From a clinical perspective, patients can be stratified into carriers and non-carriers of this risk allele to explore its impact on clinical variables, such as presentation and disease outcomes. Our goals are to elucidate the genetic pathogenesis and the clinical impact of the 8q24 variant allele on prostate cancer. The Specific Aims of this Project are to: Aim 1: To identify the causal germline allele through fine mapping of the 8q24 region Aim 2: To characterize inherited variation at 8q24 and somatic molecular associations at 8q24 Aim 3: To determine the effect of the germline 8q24 variant on clinical presentation and outcomes in prostate cancer patients