Germline Mutations in African American Families with Aggressive Prostate Cancer

 描述（由申请人提供）：非裔美国人（AA）男性的前列腺癌（PCa）死亡率是白人美国人（CA）男性的两倍，因为他们持续表现出更具侵袭性的疾病形式。然而，AA男性中导致侵袭性PCa的遗传风险因素知之甚少，因为这一领域的研究尚未得到充分探索。为了解决这一问题，我们已经招募了20个AA家族遗传性PCa在路易斯安那州南部，其中包括15个家庭与侵略性PCa，我们已经收集了样本，从421 AA个人与侵略性PCa。我们对一个患有侵袭性PCa的AA大家族的一名受影响和一名未受影响的人进行了外显子组测序，并确定了14种与该家族中的PCa表型共分离的新型非同义变体（NS-变体）。因此，我们推测，AA家族与积极PCa的遗传分析可能有助于识别的遗传因素赋予积极PCa的风险，和一个或多个14个确定的NS-变异可能有助于积极PCa的风险在AA男性遗传性甚至散发性PCa。本研究的目的是确定常见的生殖系突变赋予PCa风险，特别是在AA家庭和个人与积极的PCa，从而减少PCa相关的健康差距。在这项拟议的研究中，我们将：1）确定14种新的ns-变异中的哪一种赋予AA家族中侵袭性PCa的风险。我们将在受影响和未受影响的男性中对14种变异体进行基因分型，以确定在大多数具有侵袭性PCa的AA家族中哪种变异体与PCa共分离，以及哪种变异体在受影响的个体中具有最高的频率。这些变体将在约翰霍普金斯大学提供的另外25个AA PCa家族中进行验证。2)在14个候选基因中确定额外的变异，这些变异赋予侵袭性疾病的风险。 AA家庭中的PCa。我们将对20个AA家族中所有受影响男性的14个候选基因进行重新测序，以确定可能在AA家族和AA个体中赋予侵袭性PCa风险的其他变体。3)确定风险变异体在前列腺肿瘤发生中的功能。我们将对风险变体进行功能分析，包括RNA和蛋白质表达、细胞生长速率以及表达风险等位基因的细胞的锚定非依赖性集落形成，以确定哪种变体对AA中侵袭性PCa风险的贡献最大。从这项研究中获得的知识将促进我们对侵袭性PCa病因的理解，特别是在AA人群中。这项建议的结果可能会导致开发早期检测和早期管理的诊断工具，这些工具的风险增加，发展积极的PCa，最终减少PCa相关的健康差异。

 DESCRIPTION (provided by applicant): The mortality rate of prostate cancer (PCa) in African American (AA) men is two-folds higher that in Caucasian American (CA) men because they persistently present with a more aggressive form of the disease. However, the genetic risk factors contributing to aggressive PCa in AA men are poorly understood because this area of research has not been sufficiently explored. To address this deficiency, we have enrolled 20 AA families with hereditary PCa in southern Louisiana, including 15 families with aggressive PCa, and we have collected samples from 421 AA individuals with aggressive PCa. We performed exome sequencing on one affected and one unaffected man from a large AA family with aggressive PCa and identified 14 novel non-synonymous variants (ns-variants) that co-segregate with the PCa phenotype in this family. Therefore, we hypothesize that genetic analyses of AA families with aggressive PCa may facilitate the identification of the genetic factors conferring risk to aggressive PCa, and one or more of the 14 identified ns-variants may contribute to aggressive PCa risk in AA men with hereditary or even sporadic PCa. The objective of this study is to identify common germline mutations conferring PCa risk, specifically in AA families and individuals with aggressive PCa, thereby reducing the PCa-related health disparity. In this proposed study, we will: 1) Determine which of the 14 novel ns-variant(s) confers risk to aggressive PCa in AA families. We will genotype the 14 variants in affected and unaffected men to determine which variant(s) co-segregate with PCa in most AA families with aggressive PCa and which variant(s) have the highest frequency in affected individuals. These variants will be validated in an additional 25 AA PCa families provided by Johns Hopkins University. 2) Identify additional variants in the 14 candidate genes conferring risk to aggressive PCa in AA families. We will re-sequence the 14 candidate genes in all of the affected men in the 20 AA families to identify additional variants that may confer risk to aggressive PCa in AA families and AA individuals. 3) Determine the functions of the risk- variant(s) in prostate tumorigenesis. We will perform functional analyses of the risk-variant(s) including RNA and protein expression, cell growth rate, and anchorage-independent colony formation of the cells expressing risk-allele(s) to determine which variant(s) most strongly contributes to aggressive PCa risk in AA. The knowledge gained from this study will advance our understanding of the etiology of aggressive PCa, particularly in the AA population. Results from this proposal may lead to the development of diagnostic tools for early detection and early management of those at an increased risk of developing aggressive PCa to eventually reduce the PCa-related health disparities.