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Supplementary Figures 1-4 from A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on Markers of Their Metabolism in Normal Mucosa of Colorectal Adenoma Patients

Supplementary References from A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on Markers of Their Metabolism in Normal Mucosa of Colorectal Adenoma Patients

In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n = 92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P = 0.03) and CYP24A1 expression decreased 21% (P = 0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P = 0.01) and CYP27B1 expression increased 159% (P = 0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P = 0.13) and CaR expression increased 24% (P = 0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms. Cancer Res; 71(2); 413–23. ©2010 AACR.

Supplementary Figure Legends 1-4 from A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on Markers of Their Metabolism in Normal Mucosa of Colorectal Adenoma Patients

In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n = 92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P = 0.03) and CYP24A1 expression decreased 21% (P = 0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P = 0.01) and CYP27B1 expression increased 159% (P = 0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P = 0.13) and CaR expression increased 24% (P = 0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms. Cancer Res; 71(2); 413–23. ©2010 AACR.

To characterize the expression of the mismatch repair gene MutL-homolog 1 (MLH1) in normal colorectal crypts in humans, and assess parameters of its expression as a potential biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases, 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normal-appearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MLH1 protein, and analyzed using custom quantitative image analysis procedures. MLH1 expression in the ascending colon was, on average, 49% proportionally lower in cases than controls (P = 0.03), but there was little evidence for case-control differences in the rectum and sigmoid colon. In cases and controls, average MLH1 expression in the ascending colon tended to be lower with increased age [by 56% (P = 0.02) and 25% (P = 0.16), respectively, for those ≥55 years], and with a history of colorectal cancer in a first-degree relative (by 22% [P = 0.56] and 34% [P = 0.16], respectively). Among cases, but not controls, average MLH1 expression tended to be higher with current alcohol consumption, regular aspirin use, and higher total intakes of calcium, vitamin D, and folate. There was little indication of similar differences in the rectum. These preliminary data suggest that lower MLH1 expression in the normal colonic mucosa, at least in the ascending colon, may be associated with increased risk of incident, sporadic colorectal adenoma, as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MLH1 expression as a potential “treatable” biomarker of risk for colorectal neoplasms. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1599–609)