Heritable Risk Factors for Familial Prostate Cancer

描述(由申请人提供)： 前列腺癌是男性最常见的癌症，也是所有常见癌症中估计可遗传风险最大的。尽管如此，家族性前列腺癌的可遗传成分已被证明是复杂的，潜在的基因在很大程度上仍然难以捉摸。通过对流行前列腺癌的全基因组关联研究发现的常见的小效应变异并不能解释观察到的家族聚集性。大量的分离分析一致表明，前列腺癌的家族聚集性可以用罕见的大效应变异的遗传来最好地解释。家族性前列腺癌的发病年龄较早，在诊断较晚时有患更晚期疾病的风险。虽然孟德尔式的其他常见癌症已为人所知，但现在更复杂的情况被认为是家族性前列腺癌的基础。经过二十年使用关联方法的努力，目前的知识仍然非常有限。这促使我们的研究用一种独特的研究设计来阐明家族性前列腺癌的遗传学，该研究设计适应了遗传异质性、表型遗传、上位性和不完全外显的情景。我们假设，患有前列腺癌和有前列腺癌家族史的男性在复杂遗传性的背景下遗传了不常见的遗传风险变异。这种基因改变可能跨越一系列效应大小和频率，从反复出现的中等效应(外显性降低)风险变异，到罕见的大效应突变。我们的目标是识别家族性病例携带的潜在致病有害基因变异。为了更好地描述疾病的病因，我们将确定潜在的分子途径。我们还将评估哪些已识别的前列腺癌基因易在较早年龄、较晚阶段或确诊时Gleason评分较高时易患前列腺癌。与其他家族性癌症一样，有前列腺癌家族史的男性可以从基因测试中受益，特别是在个性化医疗的时代。我们的研究将大大推进这一领域，并进一步开发预测模型来指导临床护理。

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.