Heritable Risk Factors for Familial Prostate Cancer

家族性前列腺癌的遗传危险因素

• 批准号: 8974380
• 负责人: Jeffrey R. Smith
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974380
• 关键词: Accounting; Adopted; Age; Age of Onset; Alleles; Cancer Family; Clinical; Complex; DNA Sequence Alteration; Data; Detection; Diagnosis; Disease; Ensure; Etiology; Family; Family history of; Frequencies; Future; General Population; Genes; Genetic; Genetic Counseling; Genetic Epistasis; Genetic Heterogeneity; Genetic Load; Genetic Predisposition to Disease; Genetic Risk; Genetic screening method; Genotype; Germ-Line Mutation; Gleason Grade for Prostate Cancer; Health; Hereditary Malignant Neoplasm; Heritability; Heterogeneity; Hospitals; Inherited; International; Investigation; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Medical Records; Medical center; Mendelian disorder; Modeling; Molecular; Mutate; Mutation; Oncogenes; Organ; Outcome; Pathway interactions; Patient Care; Penetrance; Phenocopy; Polygenic Traits; Race; Recording of previous events; Recurrence; Registries; Research Design; Risk; Risk Factors; Role; Staging; Study Subject; Sum; Testing; Variant; Veterans; advanced disease; age related; base; cancer genetics; cancer risk; clinical care; cost; cost efficient; design; disorder risk; exome; exome sequencing; experience; genetic risk factor; genetic variant; genome wide association study; indexing; innovation; male; meetings; men; novel; novel strategies; personalized medicine; predictive modeling; proband; racial difference; risk variant; segregation; study population; trait; tumor registry

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer in men, and has the greatest estimated heritable risk of all common cancers. Despite this, the heritable component of familial prostate cancer has proven complex and the underlying genes have remained largely elusive. Common, small-effect variants identified through genome wide association studies of prevalent prostate cancer do not explain observed familial clustering. Numerous segregation analyses have consistently demonstrated that familial clustering of prostate cancer is best explained by the inheritance of uncommon, large-effect variants. Familial prostate cancer has an earlier age of onset, with risk of more advanced disease at a late diagnosis. While Mendelian forms of other common cancers are known, greater complexity is now believed to underlie familial prostate cancer. After two decades of effort using linkage approaches, current knowledge remains remarkably limited. This motivates our study to elucidate the genetics of familial prostate cancer with a unique study design that accommodates scenarios of genetic heterogeneity, phenocopies, epistasis, and incomplete penetrance. We hypothesize that men who develop prostate cancer and who have a family history of the disease inherit uncommon genetic risk variants in the setting of complex heritability. Such genetic alterations could span a range of effect sizes and frequency, from recurrent, moderate-effect (reduced penetrance) risk variants, to rare large-effect mutations. Our aims will identify potential causative deleterious genetic variants carried by familial cases. To better delineate the etiology of the disease, we will identify the underlying molecular pathways. We will also assess which of the identified prostate cancer genes predispose to prostate cancer at an earlier age, later stage, or greater Gleason score at diagnosis. As in other familial cancers, men with a concerning family history of prostate cancer could benefit from genetic testing, particularly in the era of personalized medicine. Our study will significantly advance the field and further develop predictive models to guide clinical care.

描述（由申请人提供）：