Grant Number:	2R01CA248857-08 Interpret this number
Primary Investigator:	Ogino, Shuji
Organization:	Brigham And Women'S Hospital
Project Title:	Spatial Immunopathological Epidemiology of Colorectal Adenoma-Carcinoma Spectrum
Fiscal Year:	2026

Project Summary/Abstract It is necessary to develop better prevention strategies against colorectal cancer (CRC), which is a major cause of cancer death. For prevention research, the colorectum provides an opportunity to study premalignant adenomas and carcinomas together. The somatic mosaicism phenomenon indicates that all of us, including cancer-free individuals, carry mutant cells/clones for decades (unless premature death occurs). Those mutant clones may lead to full-blown cancer in some individuals, while no cancer develops in others. This highlights the decades-long process of tumorigenesis and the importance of evaluating long-term time-varying risk factor exposures. Long-term lifestyles play a role in CRC prevention, as about 40-70% of CRC cases are estimated to be preventable through lifestyle modifications. Evidence also indicates immunomodulatory effects of alcohol, coffee, aspirin, and physical activity. However, most epidemiological studies using tumor profiling rely on case-control or case-only designs, where pre-diagnosis exposure data are largely unavailable, creating an intractable gap between long-term exposure analyses and tumor profiling. As a result, spatial immune cell analyses have not been fully integrated into longitudinal epidemiologic studies. To address this, we will use the prospective cohort incident-tumor biobank method (PCIBM) on the Health Professionals Follow-up Study (HPFS), Nurses’ Health Study (NHS), and NHS II (NHS2). These studies can link long-term time-varying exposures with CRC (or adenoma) incidence and tumor features. In fact, studies combining long-term time- varying exposure analyses with tumor incidence/profiling for both adenomas and CRCs are extremely rare. We will leverage such a rare opportunity in well-defined populations, which can yield unparalleled etiological insights. We will employ highly multiplexed immunofluorescence and in situ digital image analysis combined with machine learning to study the microgeometric features of thousands of CRCs and adenomas in the large prospective cohorts. Specific aims include testing whether immunosuppressive microgeometric features predict adenoma recurrence and CRC mortality, whether inverse associations of coffee, aspirin, alcohol abstinence, and physical activity with tumor incidence are stronger in tumors with higher immunosuppressive features, and whether inverse associations of those postdiagnosis lifestyle exposures with tumor recurrence and mortality are stronger in tumors with higher immunosuppressive features. Therefore, our project will generate spatial cellular organizational data to examine the interplay between lifestyle factors and tumor immune microenvironments. Our project will provide not only the immune cell landscape in the large adenoma-CRC datasets but also unique evidence for long-term time-varying exposure effects on the incidence / clinical outcomes of the adenoma-CRC spectrum. In addition, this project may reveal the timing of such effects (e.g., before and/or after adenoma detection; after CRC detection). This project will likely be able to inform strategies for improving prevention and treatment.




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