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.
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