A genomic scan of hereditary prostate cancer families with an occurrence of colon

描述(由申请人提供)： 项目摘要/摘要前列腺癌(PC)是美国最常见的非皮肤癌，但人们对其病因知之甚少。双胞胎和分离研究为遗传易感性PC提供了强有力的证据，估计42%的病例是由于一些潜在的基因改变，5%-10%是由于罕见的常染色体显性突变。遗传性前列腺癌(HPC)家系的连锁分析报告了大约12个可能含有易感基因的基因座，但由于疾病和基因座的异质性，确认一直是具有挑战性的。一种有希望的方法是专注于共享共同特征的HPC家族的子组，目标是创建一个同质子集来增强连锁能力。最近，PC和结肠癌(CC)之间出现了几种遗传关联：1)已知CC基因的遗传变异与PC的风险正相关；2)8q24上的一个基因座与PC和CC的风险增加有关。基于这些观察结果，我们假设具有CC诊断成员的HPC家系可能代表了用于连锁分析的更同质的亚群。为了研究这一假设，我们将利用前列腺癌遗传研究(PROCESS)的数据，该研究已经用421个基因组范围的微卫星标记对255个HPC家系进行了基因分型。根据基线调查和跟踪调查，我们确定了156个HPC家庭，其中包括一个或多个已被诊断为CC的成员。利用这些家系，我们将进行参数和非参数连锁分析，目的是识别一个或多个与HPC连锁的遗传基因座，假设存在多效性遗传效应，该基因座也可能在CC中发挥作用。这项工作的结果将在有希望的地区进行精细测绘，并利用先前基于人群的PC病例对照研究的现有DNA样本进行关联研究。这项拟议的研究可能会突出基因组中含有HPC易感基因的新区域，并为PC的潜在遗传流行病学提供重要的见解，包括这种常见和复杂疾病的遗传性和散发形式。项目简介美国每六名男性中就有一人在一生中被诊断出患有前列腺癌，仅在美国每年就会导致218,890例新病例和27,050例死亡。尽管前列腺癌的发病率和死亡率很高，但人们对这种疾病的原因或谁面临的风险最大知之甚少。这项研究旨在确定一个与前列腺癌易感性相关的基因组区域(S)。这项研究的结果将使人们更好地了解前列腺癌的遗传流行病学和潜在的分子生物学，并最终可能导致开发基因测试来筛选这种常见和复杂疾病的高风险人群。

DESCRIPTION (provided by applicant): Project Summary/Abstract Prostate cancer (PC) is the most common non-skin cancer diagnosed in the US, yet little is known about what causes the disease. Twin and segregation studies provide strong evidence for an inherited genetic susceptibility to PC, with an estimated 42% of all cases due to some underlying genetic alteration, and 5-10% due to rare, autosomal dominant mutations. Linkage analyses in families with a pattern of hereditary prostate cancer (HPC) have reported about a dozen loci that may harbor susceptibility genes, but confirmation has been challenging due to disease and locus heterogeneity. One promising approach is to focus on subgroups of HPC families that share a common feature, with the goal of creating a homogeneous subset to enhance power for linkage. Recently several genetic associations between PC and colon cancer (CC) have emerged: 1) genetic variants in known CC genes have been positively associated with PC risk; and 2) a locus at 8q24 has been associated with elevated risks for both PC and CC. Based on these observations, we hypothesize that HPC families with members diagnosed with CC may represent a more homogeneous subgroup for linkage analyses. To investigate this hypothesis, we will utilize data from the Prostate Cancer Genetic Research Study (PROGRESS), which has genotyped 255 HPC families with 421 genome-wide microsatellite markers. Based on baseline and follow-up surveys, we have identified 156 HPC families that include one or more members who have been diagnosed with CC. Using these families, we will perform parametric and non-parametric linkage analyses with the goal of identifying a genetic locus or loci linked to HPC that may also play a role in CC, assuming a pleiotropic genetic effect. Results from this work will be followed-up with fine mapping in promising regions and association studies using existing DNA samples from prior population-based case- control studies of PC. The proposed study may highlight novel regions of the genome that harbor susceptibility genes for HPC and provide important insights into the underlying genetic epidemiology of PC, including hereditary and sporadic forms of this common and complex disease. Project Narrative One in six men in the US will be diagnosed with prostate cancer in their lifetime, leading to 218,890 new cases and 27,050 deaths annually in the US alone. Despite the magnitude of the morbidity and mortality associated with prostate cancer, little is known about what causes this disease or who is at greatest risk. This study aims to identify a genomic region(s) linked to increase susceptibility to prostate cancer. Results from this study will lead to a greater understanding of the genetic epidemiology and underlying molecular biology of prostate cancer, and may ultimately lead to the development of genetic tests to screen for those at highest risk for this common and complex disease.