UW Today

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March 8, 2007

UW researchers challenge cancer mutation theories

When cells become cancerous, they also become 100 times more likely to genetically mutate than regular cells, UW researchers have found. The research may explain why cells in a tumor have so many genetic mutations, but could also be bad news for cancer treatments that target a particular gene controlling cancer malignancy.


The research was led by Lawrence Loeb, UW professor of pathology and biochemistry and director of the Gottstein Memorial Laboratories in Pathology. Loeb presented his research Feb. 18 at the meeting of the American Association for the Advancement of Science in San Francisco.


Most types of cancer are believed to begin with a random genetic mutation that makes a normal cell go horribly awry. This is followed by additional mutations, which endow the cancer cells with properties allowing them to grow without normal controls to become a tumor. These mutated genes would be targets for chemotherapy.


Loeb offered an alternative hypothesis: that cancer cells changed to become much more likely to mutate, taking on a “mutator” phenotype. These cells would develop dangerous genetic mutations at a much faster rate than normal cells, which might account for the high number of mutations seen in tumor cells. With the improvement of cancer-genetics technology, Loeb and his colleagues have recently been able to prove this hypothesis. They found that tumor tissue had random mutation rates up to 100 times higher than normal tissue from the same patient.


Unfortunately, these mutator cells may contribute to advanced tumors being protected from therapeutic treatments. A chemotherapy drug may target a particular oncogene, which is a gene that affects the malignancy of a particular cell. But if cancer cells are mutator cells, a single tumor may have cells with many different types of oncogenes and drug-resistant genes. That chemotherapy drug may kill off some of the cancerous cells, but millions of other cells in the tumor will live on. To be effective, a chemotherapy treatment may have to target more than one oncogene — so-called combination chemotherapy.


Loeb believes this research may eventually help physicians determine the stage and malignancy of a tumor by testing the number of its mutations. The more mutations, the further along the tumor may be in its development to malignancy or metastasis.


The work may also lead to a discovery of why cancer cells become mutator cells. If scientists understand what happens in a cancer cell that makes it become a mutator, they might be able to prevent that from happening in other cells, or slow down the mutation rate, which could delay the onset of cancer.


Loeb may be reached at laloeb@u.washington.edu.