Etiologic Heterogeneity Between Molecular Subtypes of Prostate Cancer

项目总结 这项拟议的项目调查了前列腺癌风险因素因分子而异的假设。 肿瘤的亚型。它解决了一个难题，即前列腺癌的既定风险因素比 其他类型的癌症，尽管其发病率和死亡率很高。通过对风险因素进行认证，该项目为 为初级预防工作和机械性研究奠定了基础。值得注意的是，很少有研究调查 前列腺癌分子亚型的病因差异。 在这个项目中，我们将对107,313名男性中诊断出的3,373例前列腺癌进行分子图谱分析(23% 谁是非洲裔美国人)，谁参与了卫生专业人员后续研究(HPFS)， 医生健康研究(PHS)，或南方社区队列研究(SCCS)，我们有 在癌症诊断前收集了数十年的前瞻性风险因素数据。这个项目是建立在我们以前的基础上的 研究表明，潜在的前列腺癌风险因素，如肥胖、身高和一些遗传因素 基因变异可能与常见的TMPRSS2：ERG融合的肿瘤特异性相关。至 评估具有不同致癌机制的最常见的分子亚型，我们将应用 用于(1)来自ETS家族(TMPRSS2：ERG，ETV1， ETV4、ETV5)，(2)抑癌基因PTEN的缺失，以及(3)癌基因myc的获得。 在目标1中，我们将通过以下方式生成基于人群的常见肿瘤改变患病率的数据 在诊断时的年龄和评估分子表型在细胞水平上的共存 单元格数据。在目标2中，我们将评估前列腺癌分子亚型的危险因素。我们会 确定哪些分子亚型与不可修改的风险因素相关(家族病史，获得 身高和由前列腺癌的多基因风险分数衡量的遗传风险)，可改变的风险因素 有充分的先前证据(成人肥胖症和吸烟)，以及特定亚型的新危险因素 (体力活动和胰岛素饮食模式)。在目标3中，我们将定制使用最广泛的cBio门户 癌症基因组学门户，用于分子癌症流行病学中可访问的数据共享。 该项目的影响将是产生第一个以人口为基础的、特定年龄的流行率数据 关于分子亚型及其共生：病原学与分子异质性的关系； 以及为研究界提供来自数十年跟踪调查的高质量原始数据。 重要的是，对前列腺癌病因的细微差别的理解对于减少前列腺癌的发病率是不可或缺的。 通过初级预防造成死亡负担，就像对其他肿瘤实体一样。对任何人进行认证 其他可修改的风险因素势必会产生重大影响，因为 前列腺癌伴随着全球人口的老龄化。

PROJECT SUMMARY This proposed project investigates the hypothesis that risk factors for prostate cancer differ by molecular subtype of the tumor. It addresses the conundrum that prostate cancer has fewer established risk factors than other cancer types, despite its high incidence and mortality. By credentialing risk factors, this project lays the ground for primary prevention efforts and for mechanistic research. Notably, few studies have investigated etiologic differences based on molecular subtypes of prostate cancer. In this project, we will molecularly profile 3,373 prostate tumors diagnosed among 107,313 men (23% of whom are African-American) who participate in the Health Professionals Follow-up Study (HPFS), the Physicians’ Health Study (PHS), or the Southern Community Cohort Study (SCCS) and on whom we have collected decades of prospective risk factor data prior to cancer diagnosis. The project builds on our previous work demonstrating that potential prostate cancer risk factors such as obesity, height, and some inherited genetic variants may specifically be associated with tumors with the common TMPRSS2:ERG fusion. To assess the most common molecular subtypes with different mechanisms of carcinogenesis, we will apply cutting-edge, in-situ pathology methods for (1) gene fusions from the ETS family (TMPRSS2:ERG, ETV1, ETV4, ETV5), (2) loss of the tumor suppressor PTEN, and (3) gain of the oncogene MYC. In Aim 1, we will generate population-based data on the prevalence of the common tumor alterations by age at diagnosis and assess the co-occurrence of molecular phenotypes at the cellular level with integrated single-cell data. In Aim 2, we will assess risk factors for molecular subtypes of prostate cancer. We will characterize which molecular subtypes are associated with non-modifiable risk factors (family history, attained height, and inherited risk as measured by the polygenic risk score for prostate cancer), modifiable risk factors with substantial prior evidence (adult-age adiposity and smoking), and novel risk factors for specific subtypes (physical activity and insulinemic dietary patterns). In Aim 3, we will tailor the cBioPortal, the most widely used cancer genomics portal, for accessible data-sharing in molecular cancer epidemiology. The impact of this project will be the generation of the first population-based, age-specific prevalence data on molecular subtypes and their co-occurrence; the connection between etiology and molecular heterogeneity; and the availability of high-quality original data from decades of follow-up for the research community. Importantly, a nuanced understanding of the etiology of prostate cancer is indispensable to reducing its mortality burden through primary prevention, as it has been for other tumor entities. Credentialing any additional modifiable risk factor is poised to have a significant impact, given the quickly rising burden of prostate cancer with the aging of the global population.