The Genetic Origin of Hereditary Prostate Cancer

前列腺癌是退伍军人中最常见的癌症。在全国范围内，它的死亡率是乳腺癌的76%， 癌症; 41个男人中就有一个会死于癌症。国家综合癌症网络指南， 癌症治疗已经纳入了晚期前列腺癌患者的肿瘤测序， 有前列腺癌家族史的男性的测序。它的目的是辨别继承以及 体细胞驱动因素来指导精确治疗，尽管也可能揭示家族性癌症风险。但 指导前列腺癌预后和治疗决策知识基础仍然非常有限。 尽管前列腺癌在所有常见癌症中具有最大的遗传风险，但近90% 其遗传形式仍然未知。与乳腺癌和其他常见癌症相比， 遗传性前列腺癌的原因阻碍了传统的基于家系的连锁调查。目标 这项研究的目的是进一步阐明遗传性前列腺癌的各种原因， 家族性病例对照研究设计。我们比较了独立的病例，每个病例都有很强的家族病史， 前列腺癌，筛选对照，每个人都有前列腺癌的阴性家族史。我们的目标 利用密集的遗传数据，以确定共享从共同遗传的给定疾病基因的病例。 远祖，即使他们之间的家谱关系是未知的。我们识别疾病 通过辨别病例中祖先基因组片段的过度共享， 携带具有前列腺癌高风险的突变，并识别相关的区域遗传变异， 潜在的候选因果突变。我们介绍了一种新的算法，以确定哨兵变异最好 检测所述独立风险信号，并形成临床预测模型。我们进一步描述了 遗传基因座是负责早期诊断的特点家族性疾病，一些也影响 侵略性我们在独立的家族性病例对照研究人群中进行重复研究， 从假阳性观察结果中判断为真，我们评估了额外的现有病例对照和生物库数据集， 归纳相关的意见。这项研究将改善精确肿瘤学的知识基础， 退伍军人的家庭癌症护理

Prostate cancer is the most common cancer among Veterans. Nationally, its mortality rate is 76% that of breast cancer; one in 41 men will die of it. National Comprehensive Cancer Network Guidelines for precision prostate cancer care have incorporated tumor sequencing for men with advanced-stage prostate cancer, and germline sequencing of men with a family history of prostate cancer. Its purpose is to discern inherited as well as somatic drivers to guide precision therapy, though also potentially uncovering familial cancer risks. But the knowledge base to guide prognostic and therapeutic decision-making in prostate cancer remains very limiting. Even though prostate cancer has the greatest heritable risk of all common cancers, the causes of nearly 90% of its inherited forms remain unknown. In contrast to breast and other common cancers, the broad diversity of hereditary prostate cancer's causes has impeded traditional pedigree-based investigation by linkage. The goal of this study is to further elucidate diverse causes of hereditary prostate cancer using a novel, alternative familial case-control study design. We compare independent cases, each with a strong family history of prostate cancer, to screened controls, each with a negative family history of prostate cancer. Our Aims capitalize upon dense genetic data to identify cases that share a given disease gene inherited from a common distant ancestor, even though genealogical relationships among them are not known. We identify disease genes by discerning excess sharing of ancestral genomic segments among cases, reconstructing haplotypes harboring mutations with strong risk of prostate cancer, and discerning correlated regional genetic variants and underlying candidate causal mutations. We introduce a novel algorithm to identify sentinel variants best detecting the independent risk signals, and forming a clinically predictive model. We further delineate which genetic loci are responsible for the early age of diagnosis characterizing familial disease, some also impacting aggressiveness. We employ replication across independent familial case-control study populations to discern true from false positive observations, and we evaluate additional existing case-control and biobank data sets to generalize pertinent observations. This study will improve the knowledge base for precision oncology and familial cancer care of Veterans.