Grant Number:	5R50CA274122-03 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:	2025

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.




Long-term yogurt intake and colorectal cancer incidence subclassified by Bifidobacterium abundance in tumor.
Authors: Ugai S. , Liu L. , Kosumi K. , Kawamura H. , Hamada T. , Mima K. , Arima K. , Okadome K. , Yao Q. , Matsuda K. , et al. .
Source: Gut Microbes, 2025 Dec; 17(1), p. 2452237.
EPub date: 2025-02-12 00:00:00.0.
PMID: 39937126
Related Citations

Diverging global incidence trends of early-onset cancers: comparisons with incidence trends of later-onset cancers and mortality trends of early-onset cancers.
Authors: Terashima M. , Nakayama K. , Shirai S. , Ugai S. , Lee H.Y. , Matsui H. , Mizuno H. , Tanaka S. , Song M. , Sasamoto N. , et al. .
Source: Military Medical Research, 2025-11-14 00:00:00.0; 12(1), p. 79.
EPub date: 2025-11-14 00:00:00.0.
PMID: 41239501
Related Citations

T-cell Subset Features and Distributions Evolve Across the Colorectal Precancer-Cancer Spectrum.
Authors: Takashima Y. , Dias Costa A. , Akimoto N. , Ugai T. , Bell P. , Väyrynen J.P. , Hornick J.L. , Mino-Kenudson M. , Zhong Y. , Ugai S. , et al. .
Source: Cancer Immunology Research, 2025-11-12 00:00:00.0; , .
EPub date: 2025-11-12 00:00:00.0.
PMID: 41222477
Related Citations

The early-onset cancer epidemics: evidence synthesis using the prospective cohort incident-tumor biobank method.
Authors: Ogino S. , Ugai S. , Hamada T. , Ugai T. .
Source: European Journal Of Epidemiology, 2025-10-27 00:00:00.0; , .
EPub date: 2025-10-27 00:00:00.0.
PMID: 41144114
Related Citations

Associations between Calcium Intake and T-cell Infiltration in Colorectal Tumors.
Authors: Wesselink E. , Thomas C.E. , Takashima Y. , Mizuno H. , Buchanan D.D. , Qu C. , Hsu L. , Dias Costa A. , Ugai S. , Zhong Y. , et al. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2025-09-02 00:00:00.0; 18(9), p. 561-571.
PMID: 40371912
Related Citations

Density of T-cell Subsets in Colorectal Cancer in Relation to Disease-Specific Survival.
Authors: Thomas C.E. , Takashima Y. , Buchanan D.D. , Wesselink E. , Qu C. , Hsu L. , Dias Costa A. , Gallinger S. , Grant R.C. , Huyghe J.R. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2025-07-01 00:00:00.0; 34(7), p. 1122-1133.
PMID: 40243533
Related Citations

Global Incidence Trend of Early-Onset Obesity-Related and Non-Obesity-Related Cancers.
Authors: Terashima M. , Nakayama K. , Ugai S. , Lee H.Y. , Tsukumo Y. , Suzuki E. , Mizuno H. , Song M. , Sasamoto N. , Kawachi I. , et al. .
Source: Current Oncology (toronto, Ont.), 2025-05-31 00:00:00.0; 32(6), .
EPub date: 2025-05-31 00:00:00.0.
PMID: 40558267
Related Citations

Tumor-immune partitioning and clustering algorithm for identifying tumor-immune cell spatial interaction signatures within the tumor microenvironment.
Authors: Lau M.C. , Borowsky J. , Väyrynen J.P. , Haruki K. , Zhao M. , Dias Costa A. , Gu S. , da Silva A. , Ugai T. , Arima K. , et al. .
Source: Plos Computational Biology, 2025 Feb; 21(2), p. e1012707.
EPub date: 2025-02-18 00:00:00.0.
PMID: 39965007
Related Citations

Smoking habit and long-term colorectal cancer incidence by exome-wide mutational and neoantigen loads: evidence based on the prospective cohort incident-tumour biobank method.
Authors: Hamada T. , Ugai T. , Gurjao C. , Ugai S. , Zhang X. , Haruki K. , Takashima Y. , Akimoto N. , Lau M.C. , Matsuda K. , et al. .
Source: Bmj Oncology, 2025; 4(1), p. e000787.
EPub date: 2025-06-03 00:00:00.0.
PMID: 40519220
Related Citations

The global epidemic of early-onset cancer: nature, nurture, or both?
Authors: Ogino S. , Ugai T. .
Source: Annals Of Oncology : Official Journal Of The European Society For Medical Oncology, 2024-09-16 00:00:00.0; , .
EPub date: 2024-09-16 00:00:00.0.
PMID: 39293513
Related Citations

An Empirical Dietary Pattern Associated with the Gut Microbial Features in Relation to Colorectal Cancer Risk.
Authors: Wang K. , Lo C.H. , Mehta R.S. , Nguyen L.H. , Wang Y. , Ma W. , Ugai T. , Kawamura H. , Ugai S. , Takashima Y. , et al. .
Source: Gastroenterology, 2024-08-06 00:00:00.0; , .
EPub date: 2024-08-06 00:00:00.0.
PMID: 39117122
Related Citations

An Empirical Dietary Pattern Associated with the Gut Microbial Features in Relation to Colorectal Cancer Risk.
Authors: Wang K. , Lo C.H. , Mehta R.S. , Nguyen L.H. , Wang Y. , Ma W. , Ugai T. , Kawamura H. , Ugai S. , Takashima Y. , et al. .
Source: Gastroenterology, 2024-08-06 00:00:00.0; , .
EPub date: 2024-08-06 00:00:00.0.
PMID: 39117122
Related Citations

Risk of colorectal cancer and adenoma after an appendectomy: results from three large prospective cohort studies and meta-analysis.
Authors: Zhang Y. , Khil J. , Feng X. , Ugai T. , Ogino S. , Giovannucci E. .
Source: Cancer Causes & Control : Ccc, 2024-07-27 00:00:00.0; , .
EPub date: 2024-07-27 00:00:00.0.
PMID: 39066935
Related Citations

Addressing the Rising Trend in Early-Age-Onset Cancers in Canada.
Authors: Wildgoose P. , Servidio-Italiano F. , Raphael M.J. , Slovinec D'Angelo M. , Macaulay C. , Kassam S. , Nixon N. , Perea J. , Hamilton S. , Ramjeesingh R. , et al. .
Source: Current Oncology (toronto, Ont.), 2024-07-19 00:00:00.0; 31(7), p. 4063-4078.
EPub date: 2024-07-19 00:00:00.0.
PMID: 39057175
Related Citations

Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status.
Authors: Kawamura H. , Ugai T. , Takashima Y. , Okadome K. , Shimizu T. , Mima K. , Akimoto N. , Haruki K. , Arima K. , Zhao M. , et al. .
Source: Annals Of Surgery, 2024-05-06 00:00:00.0; , .
EPub date: 2024-05-06 00:00:00.0.
PMID: 38708875
Related Citations

Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status.
Authors: Kawamura H. , Ugai T. , Takashima Y. , Okadome K. , Shimizu T. , Mima K. , Akimoto N. , Haruki K. , Arima K. , Zhao M. , et al. .
Source: Annals Of Surgery, 2024-05-06 00:00:00.0; , .
EPub date: 2024-05-06 00:00:00.0.
PMID: 38708875
Related Citations

Enrichment of Bacteroides fragilis and enterotoxigenic Bacteroides fragilis in CpG island methylator phenotype (CIMP)-high colorectal carcinoma.
Authors: Takashima Y. , Kawamura H. , Okadome K. , Ugai S. , Haruki K. , Arima K. , Mima K. , Akimoto N. , Nowak J.A. , Giannakis M. , et al. .
Source: Clinical Microbiology And Infection : The Official Publication Of The European Society Of Clinical Microbiology And Infectious Diseases, 2024-01-22 00:00:00.0; , .
EPub date: 2024-01-22 00:00:00.0.
PMID: 38266708
Related Citations