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Mol Carcinog. 2018 Nov 30. doi: 10.1002/mc.22945. [Epub ahead of print]

Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: a randomized clinical trial.

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Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.
Division of Digestive Diseases, Department of Medicine, School of Medicine, Emory University, Atlanta, GA.
Consultants in Gastroenterology, West Columbia, SC.
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH.
Winship Cancer Institute, Emory University, Atlanta, GA.
Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH.
University of North Carolina at Chapel Hill, Chapel Hill, NC.


Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1,000 IU daily) and calcium (1,200 mg daily), alone and in combination, versus placebo over one year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (p = 0.14) and 62% (p = 0.08), TGFβ1 expression increased by 41% (p = 0.25) and 78% (p = 0.14), and the TGFα/TGFβ1 ratio decreased by 25% (p = 0.31) and 44% (p = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFβ1 alone, and TGFα relative to TGFβ1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms. This article is protected by copyright. All rights reserved.


Colorectal neoplasms; DNA mismatch repair; TGFα; TGFβ1; biological markers; calcium; chemoprevention; clinical trial; vitamin D


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