Aspirin Decreases Genetic Mutations Associated With Inherited Colon Cancer

September 14, 1998

A new study suggests that aspirin will be a useful chemopreventative for Hereditary Colon Cancer patients. Aspirin may prevent the development of a particular type of common hereditary colorectal cancer in those at high risk for the disease.

Scientists at Jefferson Medical College believe they've uncovered a molecular mechanism by which aspirin interferes with colorectal cancer development in those individuals who carry particular gene mutations that makes them very likely to get the disease.

"Aspirin is a well known prophylaxis for cancer," says molecular geneticist Richard Fishel, Ph.D., professor of microbiology and immunology at the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia, who with Josef Rüschoff, M.D., of the University of Regensburg, Germany, led the research. "The new twist is that aspirin suppresses the accumulation of mutations that are the cause of a common inherited cancer." Similar mutations are found in 5-10% of sporadic colorectal, endometrial and ovarian cancers.

Their work appears September 15 in the Proceedings of the National Academy of Sciences.

Drs. Fishel, Rüschoff and their colleagues examined human colon cancer cell lines with defective mismatch repair genes, which are necessary to fix normal cell damage that occurs when cells divide and multiply. These mismatch repair genes were discovered by Dr. Fishel and Dr. Richard Kolodner (now at the Ludwig Institute for Cancer Research in San Diego) in 1993 to be the cause of the most common form of hereditary cancer known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC).

The scientists then treated the colon tumor cells with two drugs: aspirin and sulindac, which are both nonsteroidal anti-inflammatory drugs and known cancer preventatives. They found that the drugs largely suppressed the genetic instability that underlies the development of cancer in HNPCC.

"Our results appear to suggest a very simple treatment for a common hereditary cancer predisposition syndrome," Dr. Fishel says.

For a normal cell to become a tumor cell, many mutations must occur. The accumulation of multiple mutations implies genetic instability. Aspirin suppresses that accumulation of these mutations. "Even sporadic [non-hereditary] cancer may be considered to be a genetic disease because a large number of mutations must accumulate in the tumor cells," says Dr. Fishel "Aspirin screens for cells that are genetically stable, providing a true genetic selection against such forms of cancer.

"The important point here is that this [Aspirin] is an inexpensive over-the-counter drug that anyone can take. When we first discovered the connection of mismatch repair genes to hereditary cancer there was really nothing we could recommend to families besides increased [and sometimes painful] surveillance. Now we may actually be able to prevent the disease in these individuals and allow them to lead a normal life."

According to Dr. Fishel, other researchers have shown that taking aspirin reduces the incidence of sporadic colorectal cancer in the population. "That tells you that in some fraction of the population, aspirin has some efficacy. Our results would suggest that the tumors which are most affected by aspirin may arise from having damaged mismatch repair genes. In other words, you are really only suppressing the class of tumors that are caused by having these altered genes."

Non-Steroid anti-inflammatory drugs such as aspirin and sulindac are generally thought to work through the prostaglandin pathway via cyclooxygenase (COX). The study by Drs. Rüschoff and Fishel suggests that COX is not involved.

Scientists would like to find substances that reduce the effects of environmental toxicities. Aspirin looks like it will be one of them. At least for the mutations that occur as a result of specific genetic defects associated with hereditary and some sporadic tumor cells.

When mismatch repair genes go awry, the result is commonly colon cancer. Such genes are part of the intricate molecular machinery that fixes the cellular DNA when for some reason, cell replication doesn't work correctly. According to Dr. Fishel, MSH2 and MLH1 are the most frequently altered genes in HNPCC, which accounts for some 10 to 15 percent of all colorectal cancers. A mismatch of the DNA nucleotides, or building blocks, may occur during cell replication. In replication, precise nucleotide pairing is essential. In human cells, it is a protein complex containing hMSH2 that attaches to mismatched nucleotides. The cellular repair machinery, with hMLH1, then orchestrates the correction of these errors. "Without hMSH2 or hMLH1 the cellular DNA becomes unstable, errors accumulate and the result is cancer," Dr. Fishel explains.

Now the question is, will it work in humans?" says Dr. Fishel. "We already know there is some efficacy in humans. We didn't know why--this work at least partially answers that question."

"This is an important step for cancer prevention in HNPCC", says Dr. Henry Lynch of Creighton University and one of the founders of HNPCC (also called Lynch's Syndrome). "Drs. Fishel and Rüschoff's work provides a basic research foundation to helping individuals with this devastating disease."

One next step already underway is a clinical trial in Europe to study the effectiveness of higher doses of aspirin in preventing hereditary colorectal cancer. Dr. Lynch, Dr. Fishel, and Dr. John Burn (University of Newcastle, England and leader of the European Study) are currently organizing the international hereditary colorectal cancer prevention trial using aspirin.

There is a downside to aspirin and sulindac: they have already been shown to harbor some gastrointestinal toxicity and liver toxicity, respectively. "In the future, we would like to understand the specific mechanism and the exact target for the genetic suppression as well as minimize the toxicity," Dr. Fishel says. "Not everyone can take aspirin. This has to be done the right way and in consultation with a physician."

According to the American Cancer Society, colon and rectal cancer is the third most common cancer in the nation, with some 200,000 new cases diagnosed annually. Approximately 30,000 people die each year from colon and rectal cancer. Between 15-30% of colorectal cancers appear to have a hereditary origin and approximately 50% of those involve germline mutation of the human mismatch repair genes.
-end-


Thomas Jefferson University

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