Grant Number:	5R50CA274122-02 Interpret this number
Primary Investigator:	Ugai, Tomotaka
Organization:	Brigham And Women'S Hospital
Project Title:	Integration of Immunology and Microbiology Into Molecular Pathological Epidemiology of Colorectal Cancer
Fiscal Year:	2024

Summary Colorectal cancer is a heterogenous disease influenced by somatic mutations, microbiota, host immunity, and risk factor exposures, necessitating integrative research approaches to better understand the etiology. The proposed project plans to integrates immunology and microbiology into molecular pathological epidemiology (MPE) to gain insights into the interactive role of exposures, microbiota, immune cells, and tumor cells in colorectal cancer and adenoma. This project also plans to develop novel statistical and computational methods for such research. This project leverages tumor tissue datasets in various populations, including the Nurses' Health Study (NHS), NHS2, Health Professionals Follow-up Study, Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Multiethnic Cohort Study (MEC), Partners Colonoscopy Cohort (PCC), and CALGB/SWOG 80702 trials. Our multi-level databases have accumulated information on long-term lifestyle factors and tumoral features of colorectal cancer (CRC) and adenoma. Our research involves the assessment of various immune cells and microbiota in tumor tissue using multispectral assays combined with digital image analyses and machine learning algorithms. Characteristics of molecular pathology, microorganisms, and immunity in tumor tissue will shed light on the carcinogenic process. Diet and lifestyle factors will be assessed in relation to incidence of CRC (or adenoma) subtyped by microbial and/or immune features, and in relation to clinical outcomes of these tumor subtypes. The MPE approach is expected to reveal currently unknown risk and prognostic factors for CRC and early-onset CRC, the incidence of which has increased globally for uncertain reasons. Moreover, examining effects of modifiable lifestyle factors on immune cells and microorganisms in tumor tissue will open new ways to develop personalized preventive strategies. Efforts will be made to replicate findings using other independent datasets whenever possible. New statistical methods will address analytical issues such as continuous subtyping, missing biomarker data, intratumor spatial variations, high-dimensional tumor data, mediation analyses, and prediction models. Furthermore, novel computational algorithms will be developed to decipher the spatial patterns of immune cell subsets and tumor cells in the tumor microenvironment. Integrative epidemiological analyses of immunology and microbiology will generate provide the scientific foundation for exploring roles of anti-tumor immunity and microbiota in CRC development. In addition, this project will advance population cancer sciences via the development of new statistical and computational methods.