Associations between Folate and Alcohol Consumption with Colorectal Tumor Ki67 Expression in the Southern Community Cohort Study

Abstract

Folate is hypothesized to accelerate cell proliferation in colorectal cancer (CRC) by supporting DNA synthesis, while alcohol is also linked to gastrointestinal epithelial proliferation, despite biological antagonism of folate. We report associations between folate and alcohol consumption with the proliferation marker Ki67 in CRC tumors from the Southern Community Cohort Study. Tumor samples were obtained from formalin-fixed paraffin-embedded tissue blocks. The percentage of cells expressing Ki67 was measured immunohistochemically. Exposures were assessed via questionnaire pre-diagnosis. Associations were assessed via linear regression. In 248 cases (40–78 years), neither dietary folate, folic acid supplements, nor total folate intake were associated with Ki67. Folic acid supplement use was associated with Ki67 in distal/rectal tumors (β [95% confidence interval]: 7.5 [1.2-13.8], p = .02) but not proximal tumors (-1.4 [-7.1-4.3], p=.62). A positive trend for total folate was observed for distal/rectal tumors (1.6 [0.0-3.3] per 200 μcg, p-trend=.05). Heavy drinking (women: ≥1 drink/day, men: ≥2 drinks/day) was associated with higher Ki67 (6.4 [1.0-11.9], vs. nondrinkers, p=.02), especially for distal/rectal tumors (10.4 [1.6-19.1], p=.02). Negative interaction between alcohol, total folate was observed for distal/rectal tumors (p-interaction=.06). Modest associations between folate, alcohol consumption and distal/rectal tumor Ki67 expression suggest accelerated proliferation, consistent with folate’s role in DNA synthesis.

Acknowledgments

Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from the National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. Cancer data for SCCS cancer cases from West Virginia have been provided by the West Virginia Cancer Registry. The opinions expressed are those of the authors and do not necessarily represent those of the CDC or the West Virginia Cancer Registry.

Disclosure Statement

The authors report that there are no competing interests to declare.

Authors’ Contribution

Thomas Lawler: formal analysis, writing – original draft, writing – review & editing; Timothy Su: methodology, validation, investigation, writing – review & editing; Qiuyin Cai: methodology, validation, investigation, writing – review & editing, supervision; Mark D Steinwandel: data curation, writing – review & editing; Wei Zheng: writing – review & editing, formal analysis, resources, funding acquisition; Shaneda Warren Andersen: conceptualization, methodology, writing – original draft, writing – review & editing, supervision, project administration, funding acquisition

Data Availability Statement

Data are available to qualified researchers who submit a proposal via the SCCS online submission system (https://www.southerncommunitystudy.org/for-researchers.html).

Additional information

Funding

This work was supported by the National Cancer Institute at the National Institutes of Health (grant number R00 CA207848 and R01 CA255318 to SWA); the University of Wisconsin-Madison, Office of Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation and the University of Wisconsin Carbone Cancer (grant number P30 CA014520 to HH Bailey). The Southern Community Cohort Study (SCCS) is supported by the National Cancer Institute at the National Institutes of Health (grant numbers R01 CA92447, U01 CA202979 to W Zheng), including special allocations from the American Recovery and Reinvestment Act (grant number 3R01 CA092447‐08S1 to WJ Blot). The funding source had no role in the study design, in the collection, analysis, and interpretation of data, or in the decision to submit the article for publication.