Accelerating Transdisciplinary Epidemiology of Colorectal Cancer

 描述(申请人提供)：促进结直肠癌跨学科流行病学概述肿瘤进化是一个受体细胞分子变化、宿主免疫、饮食、生活方式、微生物区系和环境影响的异质过程。因此，我计划 利用我独特的跨学科专业知识，采取跨学科的方法，整合分子水平的研究、人群水平的研究设计以及对环境、饮食和生活方式的评估。我一直在发展分子病理流行病学(MPE)的跨学科领域，具有病理学和流行病学的综合优势。我将探讨两个相互关联的协同主题：(1)结直肠癌(CRC)的MPE和(2)加速跨学科流行病学。在主题1中，我将在护士健康研究(NHS)、NHS2和卫生专业人员后续研究(HPFS)中整合2500个CRC的肿瘤分子和免疫分析。我已经成功地建立了一个史无前例的关于长期暴露、肿瘤病理、微生物、分子和免疫数据以及临床结果的高维CRC数据库，以检验以下广泛的假设：(1.1)饮食、生活方式、环境和遗传因素根据分子、微生物和免疫亚型而不同地影响CRC的发病率。(1.2)结直肠癌分子特性影响对结直肠癌的免疫应答。(1.3)结直肠癌分子和免疫状态影响患者的生存和对药物或可改变的饮食、生活方式或环境因素的反应。(1.4)结直肠癌的肿瘤内异质性程度与预后差及特定的流行病学、临床和病理特征有关。我们将把我们的综合研究扩展到其他各种环境，以复制研究结果，并评估种族、社会经济和其他因素对潜在影响的修改。该项目可能会确定针对分子改变、免疫和微生物区系的潜在策略，以预防和治疗结直肠癌。我的主题2计划是：(2.1)制定研究框架、分析设计和统计方法，以解决癌症的分子和病因异质性；(2.2)发展正在举行的国际MPE会议系列，以促进无缝的跨学科整合，目标是制定“STROBE-MPE指南”；以及(2.3)与专家协同，建立新的综合跨学科模型，“因果推断-MPE”和“MPE-健康交流研究”。因此，我的目标是促进分子病理学和人口癌症科学的跨学科整合，并解决一个关键的未得到满足的需求，即整合癌症免疫、肿瘤分子特征(包括微生物区系和肿瘤内异质性)、可改变的暴露、遗传学和结直肠癌发病率和死亡的分析。我还试图解决跨学科流行病学方面的挑战，包括缺乏跨学科专家和培训计划，以及在MPE方面缺乏研究指南。我独特的资历和跨学科的研究计划不仅可以在基于人群的范围内为结直肠癌的病因提供新的见解，还可以开发新的方法/框架，以及人口癌症科学的前沿。因此，我提议的研究可能会对未来的研究、临床实践和公共卫生产生重大影响。

 DESCRIPTION (provided by applicant): Accelerating Transdisciplinary Epidemiology of Colorectal Cancer Summary Tumor evolution is a heterogeneous process influenced by somatic molecular alterations, host immunity, diet, lifestyle, microbiota, and environment. Thus, I plan to take a transdisciplinary approach integrating molecular- level research, population-level study design, and assessment of environment, diet and lifestyle, utilizing my unique interdisciplinary expertise. I have been developing the transdisciplinary field of Molecular Pathological Epidemiology (MPE) with integrated strengths of both pathology and epidemiology. I will pursue two interconnecting synergistic Themes: (1) MPE of colorectal cancer (CRC) and (2) accelerating transdisciplinary epidemiology. In Theme 1, I will integrate tumor molecular and immunity analyses in 2,500 CRCs in the Nurses' Health Study (NHS), the NHS2 and the Health Professionals Follow-up Study (HPFS). I have successfully built an unprecedented high-dimensional CRC database on long-term exposures, tumor pathology, microbial, molecular and immunity data, and clinical outcome, to test the following broad-term hypotheses: (1.1) Dietary, lifestyle, environmental and genetic factors influence CRC incidence differentially by molecular, microbial and immunity subtypes. (1.2) CRC molecular features influence immune response to CRC. (1.3) CRC molecular and immunity status influences patient survival and response to drugs or modifiable dietary, lifestyle or environmental factors. (1.4) The degree of CRC intratumor heterogeneity is associated with worse prognosis and specific epidemiologic, clinical, and pathological features. We will extend our integrative research to various other settings to replicate findings and assess potential effect modifications by ethnic, socioeconomic and other factors. This project may identify potential strategies to target molecular alterations, immunity and microbiota for CRC prevention and therapy. My Theme 2 plans are; (2.1) to develop research frameworks, analysis designs and statistical methods, to address molecular and etiologic heterogeneity of cancer; (2.2) to grow the ongoing International MPE Meeting Series, to facilitate seamless transdisciplinary integration with a goal of making "the STROBE-MPE guidelines"; and (2.3) to synergize with experts and build new integrative transdisciplinary models, "causal inference-MPE" and "MPE-health communication research". Thus, I aim to promote transdisciplinary integration of molecular pathology and population cancer science, and to address a critical unmet need to integrate analyses of cancer immunity, tumor molecular profiles (including microbiota and intratumor heterogeneity), modifiable exposures, genetics, and CRC incidence and death. I also try to address challenges in transdisciplinary epidemiology, including paucity of interdisciplinary experts and training programs, as well as lack of research guidelines in MPE. My unique qualifications and transdisciplinary research program can not only provide new insights on CRC etiologies in a population-based scale, but also develop novel methods / frameworks, and frontiers of population cancer science. As such, my proposed research will likely have major impacts on future research, clinical practice and public health.