Genetic Epidemiology of Prostate Cancer

前列腺癌的遗传流行病学

• 批准号: 7240601
• 负责人: Alice Whittemore
• 金额: $ 37.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7240601
• 关键词: 19p; 19p13.3; Abbreviations; Accounting; African American; Alleles; Androgen Receptor; Archives; Biochemical; Biological Assay; Biotechnology; Blood; California; Cancer Family; Cancer-Predisposing Gene; Caucasians; Caucasoid Race; Chromosomes; Data; Data Analyses; Data Linkages; Databases; Distal; Expressed Sequence Tags; Family; Funding; Genes; Genetic Heterogeneity; Genetic Polymorphism; Genome; Genomics; Genotype; Hawaii; Human Genome; Individual; International; Lod Score; Los Angeles; Malignant neoplasm of prostate; Molecular; Molecular Conformation; National Cancer Institute; Northern Blotting; Numbers; Participant; Polymerase Chain Reaction; Prostate-Specific Antigen; Request for Applications; Research Institute; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Reverse Transcription; Scanning; Second Degree Relative; Signal Transduction; Single Nucleotide Polymorphism; Single-Stranded Conformational Polymorphism; Stanolone; Statistical Methods; Statistically Significant; Sweden; Testing; Tissues; Transcript; Variant; Vitamin D3 Receptor; base; cancer genetics; cancer risk; case control; cohort; gel electrophoresis; genetic epidemiology; genetic linkage analysis; genetic pedigree; genetic resource; genetic variant; genome wide association study; genome-wide linkage; member

We have obtained pedigree data, blood and archived tissue from members of 98 families containing three or more confirmed cases of prostate cancer. We have typed these families for 437 autosomal markers and have analyzed the data for linkage. Although no single chromosomal region met the genome-wide criteria for statistically significant excess allele sharing, our strongest signal on the distal end of chromosome 19p has been replicated independently by a study of multiple-case prostate cancer families in Sweden (Wiklund et al. 2003). In this competing renewal application we request funds to test the hypothesis that region 19p13.3 harbors a prostate cancer susceptibility gene. Our objectives are to: 1) narrow the region by tripling the number of markers and perform linkage analysis to exclude subregions with low lod scores, using statistical methods that accommodate both individual-specific and family-specific covariates that may account for genetic heterogeneity across families; 2a) rank the 92 known genes and 61 transcripts of unknown genes in the (narrowed) region with respect to their potential involvement in prostate cancer, and 2b) identify polymorphisms in the more promising genes; 3a) investigate associations between prostate cancer risk and the variant alleles in the identified polymorphisms by genotyping 750 African-American and 750 Caucasian case-control pairs in a casecontrol study nested within the Hawaii/Los Angeles multiethnic cohort (MEC); 3b) when warranted, investigate the functional significance of these variants. The NCI-funded International Consortium for Prostate Cancer Genetics (ICPCG) is a resource of more than 1,500 multiple-case prostate cancer families. As members of the ICPCG, our long-term aim is to pursue with this group any promising leads identified in this project.

我们已经获得了98个家庭成员的系谱数据、血液和档案组织，这些家庭包含三个或更多确诊的前列腺癌病例。我们已经对这些家系的437个常染色体标记进行了分型，并对数据进行了连锁分析。虽然没有一个染色体区域满足全基因组统计上显著的过量等位基因共享的标准，但我们在19p染色体远端的最强信号已经通过对瑞典多病例前列腺癌家族的研究独立复制(Wikund等人)。2003年)。在这个相互竞争的更新申请中，我们申请资金来测试19p13.3区域含有前列腺癌易感基因的假设。我们的目标是：1)通过将标记数量增加两倍来缩小区域，并执行连锁分析，以排除LOD得分低的亚区，使用包括个体特定协变量和家庭特定协变量的统计方法，这些协变量可能解释跨家庭的遗传异质性；2a)根据(缩小的)区域中的92个已知基因和61个未知基因的转录本，对它们与前列腺癌的潜在参与进行排名；以及2b)确定更有希望的基因中的多态；3a)在夏威夷/洛杉矶多民族队列(MEC)内嵌套的病例对照研究中，通过对750名非洲裔美国人和750名高加索人病例对照配对进行基因分型，调查前列腺癌风险与已识别的多态中的变异等位基因之间的关系；3b)如果有必要，调查这些变异的功能意义。NCI资助的国际前列腺癌遗传学联合会(ICPCG)是1500多个前列腺癌家族的资源。作为ICPCG的成员，我们的长期目标是与该小组一起追查这一项目中发现的任何有希望的线索。