A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on the APC/β-Catenin Pathway in the Normal Mucosa of Colorectal Adenoma Patients

Ahearn, Thomas U.; Shaukat, Aasma; Flanders, W. Dana; Rutherford, Robin E.; Bostick, Roberd M.

doi:10.1158/1940-6207.capr-12-0292

Cited by 49 publications

(37 citation statements)

References 38 publications

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“…We cannot exclude the possibility that low 25-OHD is associated with other predictors of poor prognosis because this was an observational study. 41 in the normal mucosa of patients with colorectal adenoma, further highlighting the need to explore vitamin D as a preventative and therapeutic anticancer agent. 38 In this large study, we report for the first time an association between mortality following a diagnosis of CRC and an interaction between GAGC haplotype dose and vitamin D. Plasma 25-OHD, along with genotype at the VDR locus, has potential utility as a prognostic biomarker.…”

Section: Discussionmentioning

confidence: 99%

Plasma Vitamin D Concentration Influences Survival Outcome After a Diagnosis of Colorectal Cancer

Zgaga

Τheodoratou

Farrington

et al. 2014

JCO

130

122

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Purpose We investigated whether the plasma level of 25-hydroxyvitamin D (25-OHD) after a diagnosis of colorectal cancer (CRC) influences survival outcome. Patients and Methods We prospectively studied 1,598 patients with stage I to III CRC. We sought association between plasma 25-OHD and stage-specific survival and tested for interaction between 25-OHD level and variation at the vitamin D receptor (VDR) gene locus. Blood was sampled postoperatively, and plasma was assayed for 25-OHD by liquid chromatography-tandem mass spectrometry. VDR polymorphisms (rs1544410, rs10735810, rs7975232, rs11568820) were genotyped, and haplotypes were inferred by using BEAGLE software. We tested for association between survival and 25-OHD, VDR genotype/haplotype, and after applying a VDR genotype–25-OHD interaction term. We conducted Kaplan-Meier survival analysis and used Cox proportional hazards models to estimate adjusted hazard ratios (HRs). Results We found strong associations between plasma 25-OHD concentration and CRC-specific (P = .008) and all-cause mortality (P = .003). Adjusted HRs were 0.68 (95% CI, 0.50 to 0.90) and 0.70 (95% CI, 0.55 to 0.89), respectively (highest v lowest 25-OHD tertile), particularly in stage II disease (HR, 0.44; P = .004 for CRC-specific mortality). We detected gene-environment interactions between 25-OHD concentration and rs11568820 genotype for CRC-specific (P = .008) and all-cause (P = .022) mortality, number of protective alleles (P = .004 and P = .018, respectively), and GAGC haplotype at the VDR locus for all-cause mortality (P = .008). Conclusion In patients with stage I to III CRC, postoperative plasma vitamin D is associated with clinically important differences in survival outcome, higher levels being associated with better outcome. We observed interactions between 25-OHD level and VDR genotype, suggesting a causal relationship between vitamin D and survival. The influence of vitamin D supplementation on CRC outcome will require further investigation.

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Section: Discussionmentioning

confidence: 99%

Plasma Vitamin D Concentration Influences Survival Outcome After a Diagnosis of Colorectal Cancer

Zgaga

Τheodoratou

Farrington

et al. 2014

JCO

130

122

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“…40,41 Second, calcium has been suggested to reduce cell proliferation and promote cell differentiation and apoptosis, as a rise in extracellular calcium leads to an increase in cytosol calcium concentration of colonic epithelia cells, which in turn modulates signaling pathways related to cell cycles. [42][43][44][45] Third, given that mutations in the APC/b-catenin pathway are a common Epidemiology early hallmark in colorectal carcinogenesis and that calcium was shown to induce favorable changes in the APC/b-catenin pathway, 46 calcium may prevent the initiation of the neoplastic pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Calcium intake and colorectal adenoma risk: Dose‐response meta‐analysis of prospective observational studies

Keum

Aune

Greenwood

et al. 2014

Intl Journal of Cancer

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Evidence from randomized controlled trials suggests that calcium may protect against recurrence of colorectal adenomas, which could lead to the subsequent prevention of cancer. Yet the trials used only a large single dose and were of small sizes, and thus, knowledge of the dose-response relationship and influence on high-risk adenomas is limited. To address these issues, we conducted linear and nonlinear dose-response meta-analyses primarily based on prospective observational studies published up to July 2014 identified from PubMed and Embase. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated for total and supplemental calcium intake, respectively, using a random-effects model. For total calcium intake, summary RR for each 300 mg/day increase was 0.95 (95% CI 5 0.92-0.98; I 2 5 45%; eight studies with 11,005 cases;range of intake 5 333-2,229 mg/day). Evidence of nonlinearity was indicated: approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.92 (95% CI 5 0.89-0.94) at 1,000 mg/day and 0.87 (95% CI 5 0.84-0.90) at 1,450 mg/day (p nonlinearity < 0.01). Associations were stronger for high-risk adenomas (1 cm in diameter, (tubulo)villous histology, dysplasia, or multiplicity): approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.77 (95% CI 5 0.74-0.81) at 1,000 mg/day and reduced to 0.69 (95% CI 5 0.66-0.73) at 1,450 mg/da (p nonlinearity < 0.01). For supplemental calcium intake, summary RR of total adenoma risk for each 300 mg/day increase was 0.96 (95% CI 5 0.93-0.99; I 2 5 0%; three studies with 4,548 cases; range of supplementation 5 0-1,366 mg/day). In conclusion, calcium intake may continue to decrease the risk of adenomas, particularly high-risk adenomas, over a wide range of calcium intake.

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“…With increasing interest in vitamin D and the development of our image analysis software that allowed quantification of biomarkers that are expressed in density gradients along the colon crypt axis, we next conducted the Calcium and Vitamin D vs. Markers of Adenomatous Polyps trial (CaDvMAP) [40, 79, 80, 82–84, 90, 91]. In this pilot randomized, double-blind, placebo-controlled 2×2 factorial clinical trial we randomized 92 sporadic colorectal adenoma patients to vitamin D 3 (800 IU), calcium (2.0 g elemental calcium as calcium carbonate), both, or placebo given in two equally divided doses twice daily with meals over six months.…”

Section: 0 Modulation Of Biomarkers Of Risk For Colorectal Neoplasmmentioning

confidence: 99%

Effects of supplemental vitamin D and calcium on normal colon tissue and circulating biomarkers of risk for colorectal neoplasms

Bostick

2015

The Journal of Steroid Biochemistry and Molecular Biology

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This brief review, based on an invited presentation at the 17th Workshop on Vitamin D, is to summarize a line of the author’s research that has been directed at the intertwined missions of clarifying and/or developing vitamin D and calcium and as preventive agents against colorectal cancer in humans, understanding the mechanisms by which these agents may reduce risk for the disease, and developing ‘treatable’ biomarkers of risk for colorectal cancer. The biological plausibility and observational and clinical trial evidence for vitamin D and calcium in reducing risk for colorectal neoplasms, the development of pre-neoplastic biomarkers of risk for colorectal neoplasms, and the clinical trial findings from the author’s research group on the efficacy of vitamin D and calcium in modulating these biomarkers are summarized. Regarding the latter, we tested the efficacy of 800 IU (20 µg) of vitamin D3 and 2.0g of calcium daily, alone and combined vs. placebo over 6 months on modulating normal colon tissue and circulating hypothesis-based biomarkers of risk for colorectal neoplasms in a randomized, double-blind, placebo-controlled, 2×2 factorial design clinical trial (n = 92). The tissue-based biomarkers were measured in biopsies of normal-appearing rectal mucosa using immunohistochemistry with quantitative image analysis, and a panel of circulating inflammation markers was measured using enzyme-linked immunoassays (ELISA). Statistically significant proportional tissue increases in the vitamin D group relative to the placebo group were found in bax (51%), p21 (141%), APC (48%), E-cadherin (78%), MSH2 (179%), the CaSR (39%), and CYP27B1 (159%). In blood, there was a 77% statistically significant decrease in a summary inflammation z-score. The findings for calcium were similar to those for vitamin D. These findings indicate that supplemental vitamin D3 or calcium can favorably modulate multiple normal colon tissue and circulating hypothesis-based biomarkers of risk for colorectal neoplasms in sporadic colorectal adenoma patients.

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A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on the APC/β-Catenin Pathway in the Normal Mucosa of Colorectal Adenoma Patients

Cited by 49 publications

References 38 publications

Plasma Vitamin D Concentration Influences Survival Outcome After a Diagnosis of Colorectal Cancer

Plasma Vitamin D Concentration Influences Survival Outcome After a Diagnosis of Colorectal Cancer

Calcium intake and colorectal adenoma risk: Dose‐response meta‐analysis of prospective observational studies

Effects of supplemental vitamin D and calcium on normal colon tissue and circulating biomarkers of risk for colorectal neoplasms

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