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

患有结肠癌的遗传性前列腺癌家族的基因组扫描

• 批准号: 7474251
• 负责人: JANET L STANFORD
• 金额: $ 8.8万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-11 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474251
• 关键词: 8q24; Affect; Age; Cancer Family; Case-Control Studies; Cessation of life; Colon; Colon Carcinoma; Complex; DNA; Data; Development; Diagnosis; Disease; Family; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Screening; Genetic screening method; Genome; Genomics; Genotype; Genus Cola; Goals; Heterogeneity; Individual; Inherited; Lead; Link; MLH1 gene; MSH2 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Microsatellite Repeats; Mismatch Repair; Molecular Biology; Morbidity - disease rate; Mutation; Numbers; Oncogenes; PMS2 gene; Pattern; Play; Population; Predisposition; Relative Risks; Reporting; Risk; Role; Sampling; Scanning; Skin Cancer; Subgroup; Surveys; Susceptibility Gene; Testing; Twin Multiple Birth; Work; abstracting; base; cancer diagnosis; cancer genetics; cancer risk; follow-up; genetic association; genetic epidemiology; genetic linkage analysis; genetic variant; insight; member; men; mortality; novel; research study; segregation

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.

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，但人们对导致该疾病的原因知之甚少。双胞胎和隔离研究为 PC 的遗传易感性提供了强有力的证据，估计所有病例中 42% 是由于某些潜在的基因改变，5-10% 是由于罕见的常染色体显性突变。对具有遗传性前列腺癌 (HPC) 模式的家族进行的连锁分析报告了大约十几个可能含有易感基因的位点，但由于疾病和位点异质性，确认一直具有挑战性。一种有前途的方法是关注具有共同特征的 HPC 系列子组，目标是创建同质子集以增强链接能力。最近出现了 PC 和结肠癌 (CC) 之间的一些遗传关联：1) 已知 CC 基因的遗传变异与 PC 风险呈正相关； 2) 8q24 的基因座与 PC 和 CC 风险升高相关。基于这些观察结果，我们假设成员被诊断患有 CC 的 HPC 家族可能代表了用于连锁分析的更同质的亚组。为了研究这一假设，我们将利用前列腺癌遗传研究 (PROGRESS) 的数据，该研究已使用 421 个全基因组微卫星标记对 255 个 HPC 家族进行了基因分型。根据基线和后续调查，我们已确定 156 个 HPC 家庭，其中包括一名或多名被诊断患有 CC 的成员。利用这些家族，我们将进行参数和非参数连锁分析，目的是确定一个或多个与 HPC 相关的基因位点，这些基因位点也可能在 CC 中发挥作用，假设存在多效性遗传效应。这项工作的结果将通过使用先前基于人群的 PC 病例对照研究中的现有 DNA 样本对有希望的区域进行精细绘图和关联研究来跟进。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，并为了解 PC 的潜在遗传流行病学提供重要见解，包括这种常见且复杂疾病的遗传性和散发性形式。项目叙述 美国六分之一的男性一生中将被诊断出患有前列腺癌，仅在美国每年就会出现 218,890 例新病例和 27,050 例死亡。尽管与前列腺癌相关的发病率和死亡率很高，但人们对导致这种疾病的原因或谁面临最大的风险知之甚少。本研究旨在确定与前列腺癌易感性增加相关的基因组区域。这项研究的结果将有助于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测试的发展，以筛选那些患有这种常见且复杂疾病的最高风险的人。