Etiologic Heterogeneity Between Molecular Subtypes of Prostate Cancer

前列腺癌分子亚型之间的病因异质性

• 批准号: 10735935
• 负责人: Konrad Hermann Stopsack
• 金额: $ 75.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735935
• 关键词: Acceleration; Address; Adolescence; Adult; African American; African ancestry; Age; Aging; Androgens; Biostatistical Methods; Breast Cancer Risk Factor; Cancer Etiology; Carcinogenesis Mechanism; Cells; Cohort Studies; Common Neoplasm; Communities; Consensus; Credentialing; DNA sequencing; Data; Diagnosis; Dietary Practices; Disease; ERBB2 gene; ETV1 gene; ETV4 gene; Estrogen Receptors; Etiology; Event; Family; Family history of; Follow-Up Studies; Gene Fusion; Generations; Gleason Grade for Prostate Cancer; Health; Health Professional; Height; Heterogeneity; In Situ; In Vitro; Incidence; Inherited; Insulin-Like Growth Factor I; MYC gene; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Methods; Microarray Analysis; Molecular; Molecular Epidemiology; Molecular Epidemiology of Cancer; Molecular Profiling; Natural History; Obesity; Outcome; PSA screening; PTEN gene; Pathology; Physical activity; Physicians; Population; Population Study; Prevalence; Primary Prevention; Progesterone Receptors; Prospective, cohort study; Prostatic Neoplasms; Race; Recording of previous events; Research; Risk; Risk Assessment; Risk Factors; Selection for Treatments; Signal Transduction; Smoking; Solid Neoplasm; TMPRSS2 gene; Tissue Microarray; Tumor Subtype; Tumor Suppressor Proteins; Tumor Tissue; Validation; Work; biobank; cBioPortal; cancer diagnosis; cancer epidemiology; cancer genomics; cancer risk; cancer type; carcinogenicity; cohort; data exploration; data sharing; early onset; epidemiologic data; experimental study; follow-up; genetic variant; health data; human old age (65+); innovation; men; modifiable risk; molecular phenotype; molecular subtypes; mortality; novel; polygenic risk score; population based; prevent; prospective; prostate cancer risk; tumor; tumor DNA; tumor diagnosis; tumor heterogeneity

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.

项目概要 该拟议项目研究了前列腺癌危险因素因分子水平而异的假设。 它解决了前列腺癌的已知危险因素较少的难题。 尽管其他癌症类型的发病率和死亡率很高，但该项目通过认证风险因素奠定了基础。 值得注意的是，很少有研究对此进行调查。 基于前列腺癌分子亚型的病因学差异。 在这个项目中，我们将对 107,313 名男性（占男性的 23%）中诊断出的 3,373 种前列腺肿瘤进行分子分析。 参加卫生专业人员随访研究 (HPFS) 的非裔美国人） 医生健康研究 (PHS) 或南方社区队列研究 (SCCS) 我们对谁进行了研究 该项目建立在我们之前的癌症诊断之前收集了数十年的前瞻性风险因素数据。 研究表明潜在的前列腺癌危险因素，如肥胖、身高和一些遗传因素 遗传变异可能与具有常见 TMPRSS2:ERG 融合的肿瘤特别相关。 评估具有不同致癌机制的最常见分子亚型，我们将应用 用于 (1) ETS 家族基因融合的尖端原位病理学方法（TMPRSS2:ERG、ETV1、 ETV4、ETV5)，(2) 肿瘤抑制基因 PTEN 的丧失，以及 (3) 癌基因 MYC 的增加。 在目标 1 中，我们将通过以下方式生成有关常见肿瘤改变发生率的基于人群的数据： 诊断时的年龄并通过整合评估细胞水平上分子表型的共现 在目标 2 中，我们将评估前列腺癌分子亚型的危险因素。 描述哪些分子亚型与不可改变的危险因素（家族史、获得的 身高、遗传风险（通过前列腺癌多基因风险评分测量）、可改变的风险因素 具有大量先前证据（成年肥胖和吸烟），以及特定亚型的新危险因素 （身体活动和胰岛素饮食模式）在目标 3 中，我们将定制最广泛使用的 cBioPortal。 癌症基因组学门户，用于分子癌症流行病学的可访问数据共享。 该项目的影响将是生成第一个基于人口的、特定年龄的患病率数据 分子亚型及其共现；病因学和分子异质性之间的联系； 以及研究界数十年跟踪研究中获得的高质量原始数据。 重要的是，对前列腺癌病因的细致了解对于减少前列腺癌的发生至关重要。 通过一级预防来减轻死亡率负担，就像其他肿瘤实体一样。 鉴于快速增加的负担，额外的可改变风险因素将产生重大影响。 随着全球人口老龄化，前列腺癌。