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Scientists discover melanoma-driving genetic changes caused by sun damage
Date:7/19/2012

d by direct damage from UV light exposure.

Those known mutations are important, but don't 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.

Among the most frequently mutated genes, 85 percent of the active coding mutations resulted from C to T transitions caused by UV light exposure.

Statistical approaches to identify driver mutations have often assumed that the baseline mutation rate is uniform across the genome. The abundance of UV-induced passenger mutations that vary in frequency confounds this assumption in melanoma, the researchers report.

"When a gene is found to be repeatedly mutated, we naturally assume that it must be important to the cancer," said Garraway, who is co-senior author with Chin on the study. "However, melanoma can fool us in that cancer, the very high mutation rate means that many genes can be recurrently mutated purely by chance. We needed a solution to this problem."

To counter this effect, the researchers turned to parts of the genome that don't code for proteins, called introns, and other inactive DNA segments that flank exons. By comparing the frequency of mutations in the inactive segments to the frequency of mutations in the exons, the researchers built a framework for assessing the statistical significance of functional mutations.


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Contact: Laura Sussman
lsussman@mdanderson.org
713-745-2457
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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