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Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence.

ABSTRACT: In many cells throughout the body, vitamin D is converted into its active form calcitriol and binds to the vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D-metabolising enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating the effects of vitamin D. Preclinical and epidemiological studies have provided evidence for anti-cancer effects of vitamin D (particularly against colorectal cancer), although clinical trials have yet to prove its benefit. In addition, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses and clinical trials on vitamin D efficacy in colorectal cancer patients. In this study, we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies and discuss the links and controversies within and between the two parts of evidence.

SUBMITTER: Dou R

PROVIDER: S-EPMC4890569 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence.

Dou Ruoxu R Ng Kimmie K Giovannucci Edward L EL Manson JoAnn E JE Qian Zhi Rong ZR Ogino Shuji S

The British journal of nutrition 20160501 9

In many cells throughout the body, vitamin D is converted into its active form calcitriol and binds to the vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D-metabolising enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating the effects of vitamin D. Preclinical and epidemiological studies have provided evidence for anti-cancer effects ...[more]

PMID: 27245104

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Project description:Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality in the United States. Notwithstanding major improvements in the early detection and treatment of CRC, an important proportion of patients who received a diagnosis of localized disease ultimately have a recurrence and die, underscoring the need of new therapeutic approaches. Vitamin D and physical activity (PA) have emerged as 2 potential interventions for both prevention and treatment of CRC. Plausible biological mechanisms have been described for the antineoplastic effects of vitamin D and PA, and a wealth of epidemiological evidence indicates that 25(OH)D (the main circulating form of vitamin D) and PA levels are inversely associated with CRC risk. Recent efforts have now focused on the role of vitamin D and PA as adjunct treatments after a CRC diagnosis. Observational studies evaluating prediagnosis and postdiagnosis circulating 25(OH)D levels among patients with CRC of all stages have found that subjects with levels in the highest quantiles have improved overall and CRC-specific survival compared with those with levels in the lowest quantiles. Similarly, prospective studies of PA have found that higher levels of postdiagnosis PA are associated with lower overall and CRC-specific mortality in patients with nonmetastatic CRC. Meta-analyses of the observational studies of 25(OH)D and postdiagnosis PA have confirmed significant protective associations against overall and CRC-specific mortality, as well as significant dose-response relationships. No randomized controlled trial of vitamin D or PA using survival outcomes as endpoints has been completed to date. Two randomized, placebo-controlled trials of vitamin D in patients with metastatic CRC assessing patient survival as an endpoint are underway: the first is a phase II trial comparing high-dose vitamin D3 (8000 IU/d for 2 weeks followed by 4000 IU/d) versus standard dose (400 IU/d), and the second is a phase I-II trial comparing customized oral doses of vitamin D3 titrated to raise serum 25(OH)D levels to 80 to 100 ng/mL versus 2000 IU/d. For PA, the ongoing phase III CHALLENGE (Colon Health and Life-Long Exercise Change) study is the first randomized controlled trial using survival as an endpoint among patients with stage II-III colon cancer. The results of these trials will pave the way to more conclusive phase III trials that will provide more definitive answers about the role of these interventions in the treatment of CRC. Lastly, the advent of genomic technologies will allow identifying molecular signatures in CRC associated with improved response to vitamin D and PA and will usher in a precision medicine approach to these therapies.

Project description:BackgroundColorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinical and molecular features to identify those features unique to early-onset CRC that differentiate these patients from patients 50 years old or older.MethodsBaseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence.ResultsThis retrospective review of more than 36,000 patients with CRC showed that early-onset patients were more likely to have microsatellite instability (P = .038), synchronous metastatic disease (P = .009), primary tumors in the distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in comparison with patients 50 years old or older. Patients aged 18 to 29 years had fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35-0.90; P = .015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23-7.39; P < .0001) in comparison with other patients younger than 50 years. In patients younger than 40 years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P = .003). CMS2 was relatively stable across age groups. Early-onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24-13.74; P = .0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07-0.75; P = .019) in comparison with early-onset patients without predisposing conditions.ConclusionsEarly-onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18-29 years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40 years deserves further exploration.

Dataset Information

Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence.

Publications

Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence.

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