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.

项目摘要 该项目旨在研究前列腺癌的危险因素因分子水平不同而不同的假设。 肿瘤的亚型。它解决了一个难题，即前列腺癌的既定危险因素比 其他类型的癌症，尽管其发病率和死亡率很高。通过认证风险因素，该项目奠定了 为初级预防工作和机制研究奠定了基础。值得注意的是，很少有研究调查 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名男性中诊断出的3，373例前列腺肿瘤进行分子特征分析（23%）。 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）以及我们了解的人员 在癌症诊断之前收集了数十年的前瞻性风险因素数据。该项目建立在我们以前的 研究表明，潜在的前列腺癌危险因素，如肥胖，身高，和一些遗传性的， 遗传变异可能与具有常见TMPRSS 2：ERG融合的肿瘤特异性相关。到 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）来自ETS家族的基因融合（TMPRSS 2：ERG，ETV 1， ETV 4，ETV 5），（2）肿瘤抑制基因PTEN的缺失，和（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数据： 诊断时的年龄，并评估细胞水平上的分子表型与综合 单细胞数据。在目标2中，我们将评估前列腺癌分子亚型的风险因素。我们将 表征哪些分子亚型与不可改变的风险因素（家族史，获得 身高和遗传风险（通过前列腺癌的多基因风险评分测量），可改变的风险因素 有大量的既往证据（成年肥胖和吸烟），以及特定亚型的新风险因素 （体力活动和胰岛素血症饮食模式）。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。 这一项目的影响将是产生第一个以人口为基础、按年龄划分的流行率数据 分子亚型及其共现;病因学与分子异质性的关系; 以及研究界数十年随访的高质量原始数据的可用性。 重要的是，对前列腺癌病因学的细致了解对于减少其发病率是必不可少的。 死亡率负担，因为它已经为其他肿瘤实体的初级预防。认证任何 考虑到快速上升的负担，额外的可改变风险因素将产生重大影响。 前列腺癌与全球人口的老龄化。