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.

Public Health Relevance

I plan to conduct Molecular Pathological Epidemiology (MPE) research on colorectal cancer (CRC) tumor characteristics, to gain insights into the role of environmental, diet, lifestyle, medical, screening and genetic factors in CRC incidence, mortality and clinical outcome. I will primarily utilize the resources of the Nurses' Health Study (NHS), the Nurses' Health Study II (NHS2), and the Health Professionals Follow-up Study (HPFS). I will also accelerate the field of transdisciplinary epidemiology with the goal of advancing several fronts of population cancer sciences to reduce suffering and death from cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Unknown (R35)
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Special Emphasis Panel (ZCA1-GRB-I (M1))
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Lam, Tram K
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Dana-Farber Cancer Institute
United States
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Mehta, Raaj S; Song, Mingyang; Nishihara, Reiko et al. (2017) Dietary Patterns and Risk of Colorectal Cancer: Analysis by Tumor Location and Molecular Subtypes. Gastroenterology 152:1944-1953.e1
Hamada, Tsuyoshi; Cao, Yin; Qian, Zhi Rong et al. (2017) Aspirin Use and Colorectal Cancer Survival According to Tumor CD274 (Programmed Cell Death 1 Ligand 1) Expression Status. J Clin Oncol 35:1836-1844
Gu, Mancang; Nishihara, Reiko; Chen, Yang et al. (2017) Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells. Oncotarget 8:87379-87389
Nishihara, Reiko; Glass, Kimberly; Mima, Kosuke et al. (2017) Biomarker correlation network in colorectal carcinoma by tumor anatomic location. BMC Bioinformatics 18:304
Campbell, Peter T; Rebbeck, Timothy R; Nishihara, Reiko et al. (2017) Proceedings of the third international molecular pathological epidemiology (MPE) meeting. Cancer Causes Control 28:167-176
Mehta, Raaj S; Nishihara, Reiko; Cao, Yin et al. (2017) Association of Dietary Patterns With Risk of Colorectal Cancer Subtypes Classified by Fusobacterium nucleatum in Tumor Tissue. JAMA Oncol 3:921-927
Liu, Li; Nevo, Daniel; Nishihara, Reiko et al. (2017) Utility of inverse probability weighting in molecular pathological epidemiology. Eur J Epidemiol :
Yuan, Chen; Morales-Oyarvide, Vicente; Babic, Ana et al. (2017) Cigarette Smoking and Pancreatic Cancer Survival. J Clin Oncol 35:1822-1828
Nowak, Jonathan A; Yurgelun, Matthew B; Bruce, Jacqueline L et al. (2017) Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing. J Mol Diagn 19:84-91
Momen-Heravi, Fatemeh; Masugi, Yohei; Qian, Zhi Rong et al. (2017) Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses' health study and health professionals follow-up study. Int J Cancer 141:2471-2479

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