Genetic predictors of prostate cancer survival

项目总结/摘要 父母资助的基本科学前提是， 癌症的发展可能不同于那些导致前列腺癌死亡的因素。在此，建议的补充 该项目旨在了解种族特有的风险因素协会和机制是否有助于长期 长期存在的，对黑人男性的前列腺癌疾病负担知之甚少。拟建项目 在这种情况下，通过检查风险因素-维生素D- 以前发现与前列腺癌发病率的风险增加有关，但与前列腺癌发病率的风险降低有关。 前列腺癌死亡率主要基于来自白色男性的数据。虽然维生素与维生素C的复杂关系 D与前列腺癌的关系在白色男性中已经得到了很好的研究，但对阐明这一点的研究有限 黑人之间的关系。这是值得注意的，因为众所周知：1）发展和死亡的风险较高 与白色男性相比，黑人与白色男性在维生素D分布方面的差异 25-羟基维生素D（25（OH）D）的循环浓度-用于定义维生素D状态的代谢物 - 在黑人群体中的浓度长期较低， 多个维生素D相关基因;和3）维生素D相关基因的遗传变异的鉴定 与前列腺癌风险相关。维生素D-前列腺癌研究中持续存在的差距集中在 黑人男性可能会延续现有的差距，因为维生素D是一种可改变的因素， 前列腺致癌的分子过程。这种知识差距突出了以下方面的重要性： 癌症健康差异研究和研究翻译在减少整体癌症负担。鉴于此， 拟议的项目将实施以基因为中心的方法在父母补助金，以确定是否和 维生素D途径基因中的遗传变异（单核苷酸多态性（SNP））如何影响 在未充分研究的人群中，维生素D缺乏和前列腺癌的风险较高。 具体来说，拟议中的补充项目检查了参与维生素D合成的基因的作用 （CYP27 A1和CYP27 B1）、转运（GC）、活性（VDR和RXR）和代谢（CYP24 A1） 前列腺癌风险（目标1）和死亡率（目标2）。此外，这两个目标将包括验证分析， 在黑人男性的独立样本中鉴定的SNP关联（目标1b和2b），以及计算机分析 根据正常（Aim 1c）和恶性（Aim 1c）， 前列腺组织（Aim 2c）。这份建议书对候选人来说是一个非常有价值的职业发展机会 因为它将提供癌症基因组学和遗传流行病学方面的指导和培训，这是一个新的领域， 候选人该项目还允许候选人利用独特的丰富资源和庞大的群体 由父母资助，以解决维生素D与前列腺癌之间的巨大差距。 通过提高我们对维生素D在未充分研究的黑人男性人群中的作用的理解，来研究文献。 . 1

PROJECT SUMMARY/ABSTRACT The underlying scientific premise of the parent grant is that the risk factors and mechanisms that drive prostate cancer development likely differ from those that drive prostate cancer mortality. Here, the proposed supplement project seeks to understand whether race-specific risk factor associations and mechanisms contribute to long- standing, poorly understood excess prostate cancer disease burden among Black men. The proposed project focuses on prostate cancer risk in Black men in this context through examination of a risk factor – vitamin D – previously found to be associated with an increased risk of prostate cancer incidence, but a decreased risk of prostate cancer mortality based primarily on data from White men. Although the complex relationship of vitamin D with prostate cancer has been well-studied in white men, there is limited research focused on elucidating this relationship among Black men. This is notable given the well-established: 1) higher risk of developing and dying from prostate cancer for Black compared to White men; 2) Black-White differences in vitamin D profiles defined by circulating concentrations of 25-hydroxyvitamin D (25(OH)D) – the metabolite used to define vitamin D status – with chronically low concentrations in Black populations, and Black-White differences in genetic variants in multiple vitamin D-related genes; and 3) the identification of genetic variants in vitamin D related genes associated with prostate cancer risk. The persistent gaps in the vitamin D-prostate cancer research focused on Black men likely perpetuate existing disparities as vitamin D, a modifiable factor, is known to influence several molecular processes that drive carcinogenesis in the prostate. This knowledge gap highlights the importance of cancer health disparities research and research translation in reducing the overall cancer burden. Given this, the proposed project will implement the gene-centered approach used in the parent grant to determine whether and how genetic variants (single nucleotide polymorphisms (SNPs)) in genes from the vitamin D pathway influence prostate cancer in an understudied group at high risk for both vitamin D deficiency and prostate cancer. Specifically, the proposed supplement project examines the role of genes involved in vitamin D synthesis (CYP27A1 and CYP27B1), transport (GC), activity (VDR and RXR), and metabolism (CYP24A1) in relation to prostate cancer risk (Aim #1) and mortality (Aim #2). Additionally, both aims will include validation analyses of the identified SNP associations in an independent sample of Black men (Aims 1b and 2b), and in silico analyses to identify the functional basis for the identified SNP associations based on normal (Aim 1c) and malignant prostate tissue (Aim 2c). This proposal is a distinctly valuable career development opportunity for the candidate as it will provide mentorship and training in cancer genomics and genetic epidemiology, a new area for the candidate. This project also allows the candidate to leverage the uniquely rich resources and large cohorts assembled by the parent grant to address a considerable gap in the vitamin D-prostate cancer association literature by improving our understanding of the role of vitamin D in an understudied population of Black men. . 1