Genetic Variation in 3-Hydroxy-3-Methylglutaryl CoA Reductase Modifies the Chemopreventive Activity of Statins for Colorectal Cancer

Abstract

Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, modifies the effect of statins on serum cholesterol levels. Long-term use of statins is associated with a reduced risk of colorectal cancer (CRC) in some, but not all, studies. We genotyped variants in 40 candidate genes important for cholesterol synthesis and metabolism in a population-based case-control study of CRC involving 2,138 incident cases and 2,049 population-based controls. We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and CRC risk. Compared with nonusers, the unadjusted odds ratio of CRC among statin users with the A/A genotype of rs12654264 in HMGCR was 0.3 (95% confidence interval, 0.18-0.51) and among statin users with the T/T genotype was 0.66 (95% confidence interval, 0.41-1.06; P-interaction = 0.0012). This genetic variant (A/A genotype of rs12654264) also was associated with lower serum levels of low-density lipoprotein among all cases and controls. In colon cancer cell lines, the reduction in cholesterol levels after statin treatment was substantially stronger in cells carrying the A/A genotype, and this difference was related to alternative splicing involving the HMGCR statin-binding domain. We anticipate that these data may advance the development of personalized statin use for reducing the risk of cancer as well as cardiovascular disease among the approximately 25 million people currently using statins worldwide. Cancer Prev Res; 3(5); 597-603. ©2010 AACR.

Dysregulation of the mevalonate pathway promotes transformation

“…Exogenous MVA administered to xenograft-bearing mice was also shown to promote tumor growth (14). Finally, recent epidemiological studies have shown that patients taking certain statins for cholesterol control displayed a decreased risk of developing some cancers (15)(16)(17)(18)(19)(20)(21). Taken together, these results suggest that HMGCR may play an important role in human malignancies.…”

“…A functional SNP has been identified (rs3846662) that regulates the splicing of HMGCR (24). Interestingly, overall risk of developing colorectal cancer was recently shown to correlate with genotype at rs12654264, a SNP in linkage disequilibrium with rs3846662, in statin-users but not nonusers, suggesting that patients whose cells expressed more HMGCR-D13 did not experience as much protective benefit from statin use (21). Transcript expression of HMGCR-D13 has also been associated with a decreased cholesterol-lowering response in lymphocytes exposed to simvastatin, suggesting it is refractory to inhibition by statins (25).…”

Effects of EZH2 Polymorphisms on Susceptibility to Various Carcinomas: Evidence from 6 Publications

“…A significant association was observed between the EZH2 rs3757441 polymorphism and cancer risk under the dominant model and homozygous comparison model, indicating the individuals carrying at least one T allele at EZH2 rs3757441 had a 1.52 fold higher risk of developing cancer than did wild-type carriers. EZH2 rs3757441, an intronic SNP, may affect gene expression through several mechanisms, including splicing variants, microRNA-targeting sequences changing and binding transcription-factor sites [28][29][30]. A study from English population showed EZH2 rs3757441 C/C genotype was associated with stronger EZH2 and H3K27me3 immunoreactivity in primary colorectal cancer and this SNP may serve as a promising biomarker for EZH2-targeting agents [31].…”

A Strong Case for Personalized, Targeted Cancer Prevention

“…Although perhaps less advanced than this global approach in a phase-III clinical trial, genotyping work in other sites, including the colorectum (aspirin, celecoxib, statins), prostate (selenium), and bladder (BCG), is beginning to make headway toward personalized cancer prevention as well (26)(27)(28)(29). Similar personalized genotyping approaches are being applied in research in tobacco dependence (30) and cancer therapy (31).…”