Scientists have discovered a new way for genetic mutations lead to cancer - making the DNA adjacent sections most likely to be mutated. The chance discovery, reported in the September issue of Nature Genetics could explain the unexplained cases of colon cancer and helps in the early detection of these cancers, especially among Ashkenazi Jews.
Inheritance seems to play a role in somewhere between 15% and 50% of colon cancers and benign polyps which are often precursors. However, the genes of colon cancer found up to now have been linked to less than 5% of the total cases. A hint of what could explain the discrepancy came to light when a social visitor Bert Vogelstein laboratory at the School of Medicine at Johns Hopkins University mentioned that he had multiple colorectal polyps and mild family history of colon cancer. As a courtesy, Vogelstein, whose lab had already discovered a handful of genes involved in the disease, proposed to test the 39-year-old man for known mutations.
Vogelstein, Kenneth Kinzler, and other colleagues found a minor change in the CPA gene that normally keeps cell growth in check and can cause colon cancers when mutated. At first glance, the change appears to be harmless - a simple switch from a thymine (T) to adenine (A). Such changes of genes, called polymorphisms, are common. But curiously, the tumor suppressor protein made by the gene began to pick up additional mutations in and around the area that contains the T-to-A switch. Does it seem to come Kinzler said, because the mutation creates a stretch of eight straight As, which can get rid of the enzyme that transcribes DNA and completely garble the resulting protein.
The team guessed that the A chain could also confuse the enzyme that copies DNA when cells replicates, creating new - and more damaging - mutations. Indeed, all the tumors of patients who have worn this particular T mutation also had additional mutations that inactivate the CPA gene. But the blood cells from the same patients had only to change A T - suggesting that patients have inherited the basis for change and develop other changes later, but only in colon cells that have become cancerous
". This could be a historical study of a new mechanism," says molecular biologist Jeffrey Trent of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. Trent and others say that the same mechanism could be at work in the genes linked to other cancers, such as breast cancer and prostate cancer, which were found to contain similar variations "harmless" sequence
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