Pilot investigation of treatment effect modification by vitamin D binding protein isoforms on calcium and vitamin D effects on biomarkers of risk for colorectal cancer in the normal-appearing colorectal mucosa of colorectal adenoma patients Open Access
Rago, Patrick (Fall 2021)
Abstract
Vitamin D exposure and/or calcium intake associations with colorectal adenoma, incident colorectal cancer (CRC), and CRC survival, and supplemental vitamin D3 and/or calcium effects on the expression of COX-2 and 15-PGDH (biomarkers of inflammation) in the morphologically-normal colorectal mucosa of sporadic colorectal adenoma patients were reported to be stronger among individuals with the vitamin D binding protein (VDP)-2 isoform, encoded by GC rs4588*CA or AA. The expression of proteins (APC, β-catenin, E-cadherin, MSH2) encoded by colorectal carcinogenesis pathway genes, cell cycle biomarkers (mib-1, p21, bcl-2, bax), and transforming growth factors (TGF-α, TGF-β1) in the morphologically-normal colorectal mucosa were estimated to be associated with colorectal adenoma and to be modifiable by supplemental vitamin D3 and/or calcium. However, whether these agents’ effects on these biomarkers differ by VDP isoform is unknown. To address this, using mixed linear models, we analyzed data on the expression of these 10 biomarkers (measured using automated immunohistochemistry and quantitative image analysis at baseline and 1-year follow-up) in rectal biopsies from a subset of 62 sporadic colorectal adenoma patients in a previously-conducted, placebo-controlled, chemoprevention trial of supplemental calcium (1,200 mg/day) and/or vitamin D3 (800 I.U./day) , overall and stratified by VDP isoforms (no VDP-2 [GC rs4588*CC] vs. VDP-2 [GC rs4588*CA or AA]). The findings from this pilot study were not statistically significant; however, for all active treatments relative to placebo, among those with the VDP-2 isoform, whole crypt MSH2, mib-1, bax, and bcl-2 expression was estimated to decrease and the p21/mib-1 ratio (in the upper 40%, or differentiation zone, of crypts) was estimated to increase more, whereas among those without the VDP-2 isoform, whole crypt E-cadherin expression increased more. Estimated changes in whole crypt APC, β-catenin, and TGF-β 1 expression did not substantially differ by VDP isoform. These pilot study results suggest that supplemental vitamin D3 and/or calcium effects on the expression of multiple biomarkers of risk for colorectal neoplasms in the morphologically-normal colorectal mucosa of colorectal adenoma patients may depend on someone’s VDP isoform (with effects generally stronger among VDP-2 isoform individuals), and supports a larger trial to test this hypothesis.
Table of Contents
TABLE OF CONTENTS
Pilot investigation of treatment effect modification by vitamin D binding protein isoforms on calcium and vitamin D effects on biomarkers of risk for colorectal cancer in the normal-appearing colorectal mucosa of colorectal adenoma patients.................................................1
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Pilot investigation of treatment effect modification by vitamin D binding protein isoforms on calcium and vitamin D effects on biomarkers of risk for colorectal cancer in the normal-appearing colorectal mucosa of colorectal adenoma patients () | 2021-12-06 01:22:58 -0500 |
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