New approach sorts cancer driver mutations from abundant but irrelevant passengers

Newswise HOUSTON Its been a burning question in melanoma research: Tumor cells are full of ultraviolet (UV)-induced genetic damage caused by sunlight exposure, but which mutations drive this cancer?

None have been conclusively tied to melanoma. The sheer abundance of these passenger mutations has obscured the search for genetic driver mutations that actually matter in melanoma development and progression.

By creating a method to spot the drivers in a sea of passengers, scientists at the Broad Institute of MIT and Harvard, the Dana-Farber Cancer Institute and The University of Texas MD Anderson Cancer Center have identified six genes with driving mutations in melanoma, three of which have recurrent hotspot mutations as a result of damage inflicted by UV light. Their findings are reported in the July 20 issue of the journal Cell.

Those three mutations are the first smoking gun genomic evidence directly linking damage from UV light to melanoma, said co-senior author Lynda Chin, M.D., Professor and Chair of MD Andersons Department of Genomic Medicine. Until now, that link has been based on epidemiological evidence and experimental data.

This study also is exciting because many of the recent large-scale genomic studies have not discovered new cancer genes with recurrent hot-spot mutations, a pattern strongly indicative of biological importance, said Chin, who also is scientific director of MD Andersons Institute for Applied Cancer Science.

The six new melanoma genes identified by the team are all significantly mutated and provide potential targets for new treatments.

Puzzle has thousands of potential pieces, but only requires a few dozen A number of important mutations had previously been identified as melanoma drivers. These include BRAF (V600) mutations, present in half of all melanomas, and NRAS (Q61) mutations. However, the vast majority of these mutations do not appear to be caused by direct damage from UV light exposure.

Those known mutations are important, but dont tell the whole story. Melanoma, the authors note, has higher genetic mutation rates than most other types of solid tumors. The majority are attributable to passenger mutations caused by UV light damage resulting in a DNA alteration called a cytidine (C) to thymidine (T) transition.

Chin together with Levi A. Garraway M.D, Ph.D., associate professor at Dana-Farber Cancer Institute and Harvard Medical School and senior associate member at the Broad Institute, sequenced the exons active portions of DNA involved in protein synthesis in 121 melanoma samples paired with normal DNA and found 86,813 coding mutations. The resulting mutation rate was higher than that ever reported in any other tumor type.

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Scientists Discover Melanoma-Driving Genetic Changes Caused by Sun Damage

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