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

描述（由申请人提供）： 前列腺癌（PC）是美国最常见的非皮肤癌，但对导致这种疾病的原因知之甚少。双胞胎和分离研究为PC的遗传易感性提供了强有力的证据，估计42%的病例是由于一些潜在的遗传改变，5-10%是由于罕见的常染色体显性突变。在具有遗传性前列腺癌（HPC）模式的家族中进行的连锁分析已经报道了大约十几个可能含有易感基因的位点，但是由于疾病和位点异质性，确认具有挑战性。一个有前途的方法是专注于HPC家族的子组，共享一个共同的功能，创建一个同质的子集，以提高连接的权力的目标。最近出现了PC和结肠癌（CC）之间的几种遗传关联：1）已知CC基因中的遗传变异与PC风险呈正相关; 2）8 q24位点与PC和CC的风险升高相关。基于这些观察结果，我们假设，HPC家庭成员诊断为CC可能代表一个更同质的亚组进行连锁分析。为了研究这一假设，我们将利用来自前列腺癌遗传研究（PROGRESS）的数据，该研究对255个HPC家族进行了基因分型，其中包括421个全基因组微卫星标记。根据基线和随访调查，我们已经确定了156个HPC家庭，其中包括一个或多个被诊断为CC的成员。使用这些家庭，我们将进行参数和非参数的连锁分析，以确定一个或多个遗传位点的HPC，也可能在CC中发挥作用，假设一个多效性的遗传效应。这项工作的结果将在有希望的区域进行精细定位，并使用来自先前基于人群的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强调基因组中含有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见解，包括这种常见而复杂疾病的遗传性和散发性形式。在美国，每六名男性中就有一人在其一生中被诊断出患有前列腺癌，仅在美国，每年就有218，890例新发病例和27，050例死亡。尽管与前列腺癌相关的发病率和死亡率很高，但人们对这种疾病的病因或谁的风险最大知之甚少。这项研究旨在确定与前列腺癌易感性增加相关的基因组区域。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，并可能最终导致基因检测的发展，以筛选这种常见和复杂疾病的最高风险人群。

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.