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

基本信息

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
项目类别：
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

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

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项目摘要

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）是美国诊断出的最常见的非皮肤癌，但对导致该疾病的原因知之甚少。双胞胎和隔离研究为遗传遗传易感性PC提供了有力的证据，估计由于某些潜在的遗传改变，所有病例的42％，而由于罕见的常染色体显性占主导地位突变，估计为5-10％。具有遗传性前列腺癌（HPC）模式的家庭中的连锁分析报告了可能具有易感基因的十二个基因座，但由于疾病和基因座异质性，确认是具有挑战性的。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，目的是创建一个同质子集以增强链接的力量。最近出现了PC与结肠癌（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）第8季度的一个基因座与PC和CC的风险升高有关。基于这些观察结果，我们假设患有诊断为CC的成员的HPC家庭可能代表更均匀的亚组用于连锁分析。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，该研究已经基因分型为具有421个全基因组微卫星标记的255个HPC家族。根据基线和随访调查，我们确定了156个HPC家庭，其中包括一个或多个被诊断为CC的成员。使用这些家族，我们将执行参数和非参数连锁分析，目的是识别与HPC相关的遗传基因座或基因座，假设有多效遗传效应，则可能在CC中发挥作用。这项工作的结果将在有希望的区域进行精细映射，并使用现有基于人群的PC的病例对照研究中的现有DNA样品进行精细映射。拟议的研究可能会突出具有HPC易感基因的基因组的新区域，并为PC的潜在遗传流行病学提供了重要的见解，包括这种常见和复杂疾病的遗传性和零星形式。美国六分之一的项目叙述将在其一生中被诊断出患有前列腺癌，仅在美国，每年将导致218,890例新病例和27,050例死亡。尽管与前列腺癌的发病率和死亡率相关，但对导致这种疾病或最大风险的原因知之甚少。这项研究旨在确定与增加前列腺癌敏感性相关的基因组区域。这项研究的结果将导致对前列腺癌的遗传流行病学和潜在的分子生物学有更深入的了解，并最终可能导致遗传检测的发展，以筛查这种常见和复杂疾病的最高风险的人。