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Researchers Identify Gene Variants That Protect Against Colorectal Cancer with Statin Use

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Originally published May 3.

By Turna Ray

A recent study by researchers at New York-Presbyterian Hospital and Weill Cornell Medical Center sheds light on the genetic underpinnings for why the use of cholesterol-lowering drugs by some protects them against colorectal cancer.

In the May issue of Cancer Prevention Research, Steven Lipkin and colleagues found that in colon cancer cell lines, the protective effect against colorectal cancer was stronger in cells with a particular SNP in the HGMCR gene, also a key enzyme in cholesterol synthesis. Specifically, the team found that carriers of the A/A HMGCR genotype produce more of the full-length protein that binds with statins, while the protein produced by the "T" allele does not bind to the statin as well due to alternative splicing.

The reduction in cholesterol levels after statin treatment was also substantially stronger in cells carrying the A/A genotype, the researchers reported.

"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," the researchers concluded.

More specifically, the researchers' analysis suggests that approximately 44 percent of Caucasians with an A/T genotype taking statins will not be protected against colorectal cancer. The researchers recommended physicians should give statins to those with the A/A genotype, but they also suggested the development of a new class of statins for those with other genotypes.

Although no statin developers have yet expressed an interest in these findings, the researchers plan to validate their initial data in a study being conducted by the National Cancer Institute. Lipkin told Pharmacogenomics Reporter this week that the NCI's National Surgical Adjuvant Breast and Bowel Project cooperative group is performing a randomized controlled trial of the statin Crestor (rosuvastatin calcium) for colon cancer prevention. "We will perform genotyping of the patient samples in this study to validate our findings in this additional trial," Lipkin said.

If the NCI results validate the findings, Lipkin said he wouldn't rule out an updated indication for this class of statin drugs to note their cancer-prevention properties in certain genetically defined subpopulations.

In the Cancer Prevention Research study, Lipkin et al. genotyped study participants — 1,780 northern Israeli colon cancer patients and 1,863 predominantly Caucasian controls without cancer — for 40 candidate genes that had previously been linked to the synthesis and metabolism of cholesterol.

Among the 40 candidate genes were six SNPs within HMGCR that researchers identified as producing a key enzyme involved in formation of cholesterol. Follow-up pharmacogenetic analysis suggested that one SNP within HMGCR, the "A" SNP allele, was significantly associated with statin protection.

Comparatively, those with a "T" allele did not experience as strong protection against colorectal cancer from statin use.

"Because a person inherits two variants, one from each parent, the stronger colorectal cancer protection came from individuals with the A/A HMGCR genotype, compared with those with the T/T genotype," the study authors said in a statement. "Individuals with an A/T genotype had intermediate protection against colorectal cancer — levels that varied between that seen for A/A and T/T genotypes."

In the Caucasian population in the study, 56 percent had at least one "A" allele in that HMGCR genomic position, giving them either strong or intermediate statin protection against colorectal cancer.

In investigating why people with a "T" allele had reduced colorectal cancer protection after statin use, the researchers found that those carriers produce a slightly altered protein that does not bind to the statin like the protein produced by A allele carriers.

"Carriers of the A allele express more of the full-length protein that binds statins, and are therefore more sensitive to statins and are more likely to experience the colorectal cancer risk reduction associated with long-term use. That is especially true if a person has two A alleles," Lipkin said in a statement. "Carriers of the T allele are less sensitive to statins because they are missing part of the protein that binds to statins. A protective effect against colorectal cancer development is largely absent from people who have two T alleles."

Most patients in the study were giving simvastatin, marketed under the brand name Zocor, and pravastatin, or Pravachol. According to Lipkin, the study suggests that most of the marketed statin drugs work by binding to the HMGCR protein.

The study was funded by the National Cancer Institute, the Spanish Secretaria de Estado de Universidades e Investigación, and the Ravitz Foundation, as well as with a grant from the University of Michigan Cancer Center.

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