PracticeUpdate: Haematology & Oncology

EDITOR’S PICKS 6

Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas By Sonia S. Kupfer, MD, Marc Bissonnette, MD, Yan-Chun LI, PhD V itamin D regulates a plethora of biological processes mediated by

potentially important associa- tions but lacks the ability to make causal connections, emphasising the challenges of determining underlying mechanisms when studying interventions such as vi- tamin D in colon cancer preven- tion. Crispr-Cas9 genetic tools that are capable of making alter- ations to single DNA bases could be used to dissect molecular al- terations regulated by SNPs. 10,11 When applied to model systems or genetically engineered mice, such studies could determine whether targeted SNPs regulate VDR gene expression and vita- min D effects on colon cancer development. Such insights from cell and mouse models could strengthen the rationale to un- dertake chemoprevention studies in populations expressing SNPs predicted to respond to anti-can- cer effects of vitamin D or other agents. If such investigations are successful, we would be much closer to practicing personalised medicine. References 1. Carlberg C. Front Physiol 2014;5:167. 2. Lee JE, Li H, Chan AT, et al. Cancer Prev Res (Phila) 2011;4:735-743. 3. Lamprecht SA, Lipkin M. Nat Rev Cancer 2003;3:601-614 4. Dougherty U, Mustafi R, Sadiq A, et al. Clin Cancer Res 2014;20:5848-5859. 5. Zheng W, Wong KE, Zhang Z, et al. Int J Cancer 2012;130: 10-19. 6. Baron JA, Barry EL, Mott LA, et al. N Engl J Med 2015;373:1519-1530. 7. Kupfer SS, Li YC, Bissonnette. Nutr Cancer 2017;69(1):167. 8. Kang EY, Martin L, Mangul S, et al. Genetics DOI:1534/ genetics.115.177246. 9. Kupfer SS, Torres JB, Hooker S, et al. Carcinogenesis 2009;30:1353-1357. 10. Courtney DG, Moore JE, Atkinson SD, et al. Gene Ther 2016;23(1):108-112. 11. Beaudoin M, Gupta RM, Won HH, et al. Arterioscler Thromb Vasc Biol 2015;35:1472-1479. Dr Kupfer is Assistant Professor in the Section of Gastroenterology and Director of the Gastrointestinal Cancer Risk and Prevention clinic at the University of Chicago; Dr Bissonnette and Dr Li are Associate Professor of the Department of Medicine – Section of Gastroenterology, Cancer Research Centre and on the Committee on Molecular

examined 41 candidate SNPs in genes associated with vitamin D and calcium signalling. The in- vestigators identified two SNPs in the 3’ untranslated region (UTR) of VDR (rs7968585 and rs731236) in linkage disequilibri- um that varied significantly with effects of vitamin D3 supplemen- tation on advanced adenoma oc- currence. For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementa- tion reduced advanced polyp risk by 64%, whereas in those with 1 or 2 G alleles (74%), vitamin D3 supplementation increased advanced polyp risk by 41%. Therefore, the authors specu- lated that effects of vitamin D supplementation are dependent on VDR genotype. The effects of the SNPs were not related to changes in serum vitamin D lev- els, suggesting that these SNPs modulate risk independent of serum vitamin D levels. More work is obviously needed to determine the mechanisms of these genotypic effects. SNPs in the 3’ UTR could, for example, alter mRNA splicing or microR- NA binding, modulating mRNA stability or translational effi- ciency. This study has identified

the vitamin D receptor (VDR) and is postulated to inhibit colon cancer development. 1–5 However, a recent study of vitamin D and calcium intervention by Dr Baron’s group failed to support this hypothesis, with no differences in polyp recurrence noted in individuals randomised to vitamin D and/or calcium compared with those randomised to placebo. 6 Caveats were noted with the study, including the dose of vitamin D. 7 Growing evidence supports the hypothesis that single nucleo- tide polymorphisms (SNPs) can modulate gene expression and colon cancer risk. 8,9 To further explore potential confounders for the negative results, the authors

Such insights from cell and mouse models could strengthen the rationale to undertake chemoprevention studies in populations expressing SNPs predicted to respond to anti- cancer effects of vitamin D or other agents. If such investigations are successful, we would be much closer to practicing personalised medicine.

Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas: a randomized clinical trial JAMA Oncol 2016 Dec 15;[EPub Ahead of Print], EL Barry, JL Peacock, JR Rees, et al. Take-home message • In this randomised, double-blind, multisite study, 41 single-nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes were analysed in patients with colorectal adenomas. Based on data from 1702 non-Hispanic whites, two SNPs (rs7968585 and rs731236) in vitamin D receptors were significantly linked to the impact of vitamin D3 supplementation. Vitamin D3 supplementation decreased risk for advanced adenomas by 64% among individuals with the AA genotype (26%) at the rs7968585 SNP. Risk increased by 41% in individuals with one or two G alleles (74%). The benefits of supplementation with calcium were not significantly linked to genotype. • For the prevention of advanced colorectal adenomas, the benefits of vitamin D3 supplementation may vary based on the vitamin D receptor genotype.

Metabolism and Nutrition, The University of Chicago.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY