Multidisciplinary Study of Folate Intake and Colorectal Cancer

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Project Summary / Abstract Colorectal cancer (CRC) remains one of the leading cause of cancer-related deaths in the United States. Long-term diet plays an important role in cancer prevention, as it can take decades for normal cells to become a malignant tumor, but the role of folate in CRC development and progression is unclear. Folate functions as an essential one-carbon donor for DNA synthesis and methylation and is involved in DNA damage repair during carcinogenesis, but human and animal studies report mixed findings on folate and CRC risk. Specifically, researchers have not reached consensus on 1) how short- and long-term folate intakes are associated with colorectal carcinogenesis; 2) potential underlying mechanisms, and 3) the degree to which such associations may differ by major sources of folate intake (e.g., vegetables, fruits, fortified foods, or supplements). Furthermore, the relationship between folate intake and survival among CRC patients remains to be elucidated, and no one has investigated folate intake with CRC risk and survival by integrating whole- exome sequencing (WES) data into population-based cohort studies. The objective of this proposal is to rigorously address these knowledge gaps on folate intake and CRC development and progression by leveraging existing data with an innovative approach that integrates WES of tumor and normal DNA pairs from 1,146 CRC patients in three large prospective cohort studies—the Nurses’ Health Study (NHS), the NHS II, and the Health Professionals Follow-up Study. Our central hypotheses are 1) Higher intake of folate before CRC diagnosis can prevent DNA mutations during cancer development, and 2) Higher post-diagnosis intake of folate is associated with CRC mortality for tumors with such DNA changes. We will test these hypotheses in two specific aims: 1) Evaluate folate’s chemopreventive role by timing and sources in relation to exome-wide DNA change patterns in CRC; and 2) Assess DNA change patterns as potential biomarkers indicating the survival benefit associated with post-diagnosis higher intake of folate in CRC patients. Our data of well- validated assessments of diets measured every 4 years for > 30 years is particularly valuable for examining long-term folate intake with genomic features of defective DNA damage repair in CRC. We will assess genomic features of DNA damage based on copy number, variation burden, and mutational signatures utilizing WES data. This research is innovative in defining molecular subtyping of CRC based on DNA change patterns that will refine risk estimates for specific CRC subtypes and provide more evidence for the relationship between folate intake and specific subtypes. The contribution is significant because these expected discoveries would facilitate design of dietary guidelines on timing and sources of folate intake for CRC prevention, support innovative dietary intervention programs among patients with CRC diagnosis, and lay the groundwork for nutrigenomics studies that further elucidate the role of diet in carcinogenesis.