Caucasian Cancer Resistance To Statins Traced To Gene Variant

The cholesterol drug statin could protect many against colorectal cancer too, but Caucasians are out of its reach. A gene variant in them somehow renders them impervious to statin effect.

The cholesterol drug statin could protect many against colorectal cancer too, but Caucasians are out of its reach. A gene variant in them somehow renders them impervious to statin effect, as many as 44 per cent of them in a recent study.

In the May issue of Cancer Prevention Research, researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical Center say this finding might help personalize the use of statins, both by offering patients a test to determine if they have the "right" gene to benefit from current statin drugs, and by providing insight into how to create a new class of statins for those who have the "wrong" gene profile.

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"Given that approximately 25 million individuals worldwide currently use statins, we anticipate this discovery may prompt development of more precise, personalized and cost-effective cancer risk reduction strategies," says the study's co-lead author, Dr. Steven M. Lipkin, associate professor of medicine and of genetic medicine at Weill Cornell Medical College and a geneticist and internist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

The other lead author is Dr. Stephen B. Gruber, professor of internal medicine, epidemiology and human genetics at the University of Michigan Medical School. The research team also includes scientists from the University of Barcelona, the National Cancer Institute and the Israel Institute of Technology.

The researchers tested their hypothesis that people who don't respond well to the cholesterol-lowering ability of statins also do not benefit from recently documented protective effects of statins against colorectal cancer, and that the difference was in genetic variation that led to a different response to the drug.

In this study, the research team genotyped 40 candidate genes known to be important for synthesis and metabolism of cholesterol in people who participated in a population case-control study of colorectal cancer in northern Israel. Included were 1,780 colon cancer patients and 1,863 people who did not have colorectal cancer, and many of the participants, who were predominantly Caucasian, had used statins for a long time. In the initial study, statin use was associated with a 50 percent relative risk of developing colorectal cancer in this population.

Included in the 40 genes were six SNPs, or DNA sequences, within the HMGCR gene, which produces a critical enzyme involved in formation of cholesterol.

They found one SNP within HMGCR that was associated with statin protection against colorectal cancer. A follow-up pharmacogenetic analysis showed that the protective association was significantly stronger among individuals with what they dubbed the "A" SNP allele, or variant, compared with people who had a "T" variant. 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. 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.

Dr. Lipkin estimates that, in this Caucasian population, 56 percent had at least one A allele in that HMGCR genomic position.

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They then tested, in laboratory colorectal cancer cells, why the T allele might not work well with statins, and found that the protein produced by this HMGCR gene variant does not bind on to the statin like the A allele does, due to "alternative splicing" -- the production of a protein that is slightly altered.

"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," says Dr. Lipkin. "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."

"Together, these studies provide strong evidence that these two alleles play an important role in modulation of HMGCR activity for colorectal risk reduction," Dr. Lipkin says. "We anticipate that genotyping for these alleles in patients may help identify those who are most likely to benefit from statins, and spare others who will not respond from any side effects of the drugs."

Dr. Lipkin believes most of the many statin drugs on the market work by binding on to the HMGCR protein. Most of the participants in this study used simvastatin (marketed under the trade names Zocor, Simlup, Simcard, Simvacor, and others), and pravastatin (marketed as Pravachol or Selektine).

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