Melanoma – the deadliest and most aggressive form of skin cancer – has long been linked to time spent in the sun. Now a team led by scientists from the Broad Institute and Dana-Farber Cancer Institute has sequenced the whole genomes of 25 metastatic melanoma tumors, confirming the role of chronic sun exposure and revealing new genetic changes important in tumor formation.

In an article published online May 9 in Nature, the authors provide the first high-resolution view of the genomic landscape of human melanoma tumors. Previous genetic analyses have focused on the exomes of many types of cancer tumors, concentrating on the tiny fraction of the genome that provides the genetic code for producing proteins. Whole genomes contain a wealth of genetic information, and by sequencing and analyzing 25 metastatic melanoma tumors – a significant technical and computational feat – scientists can learn vastly more about the variety of genetic alterations that matter in melanoma.

“Sequencing the whole genome certainly adds a richness of discovery that can’t be fully captured with a whole exome,” said Levi A. Garraway, a senior associate member of the Broad Institute, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School, and co-senior author of the paper.

“By looking across the entire genome you can more accurately determine the background mutation rate and the different classes of mutations, and more confidently describe the pattern of ultraviolet-induced mutagenesis in melanoma,” said Michael F. Berger, co-first author of the paper. He worked in the Broad’s cancer genome analysis group and with Garraway as a research scientist and computational biologist before moving to Memorial Sloan-Kettering Cancer Center.

When the scientists explored the whole genome data generated and analyzed at the Broad, they found that the rates of genetic mutations rose along with chronic sun exposure in patients, confirming the role of sun damage in disease development.

“Whole-genome analysis of human melanoma tumors shows for the first time the existence of many structural rearrangements in this tumor type,” said Lynda Chin, a senior associate member of the Broad and co-senior author of the paper. Formerly at Dana-Farber and Harvard Medical School, she is now chair of the Department of Genomic Medicine at the University of Texas MD Anderson Cancer Center.

As expected, the scientists detected known BRAF and NRAS mutations in 24 of the 25 tumors. Both genes are involved in sending signals important in cell growth.

One other gene leaped out: PREX2, previously implicated in breast cancer for blocking a tumor-suppressor pathway, was altered in 44 percent of patients. In a larger validation cohort of 107 tumors, the frequency of the mutation was 14 percent.

PREX2 is mutated in a convergence of genetic disruption that appears to accelerate tumor development. Its mutations occurred not just at hot spots that typically turn on an oncogene, a type of cancer-causing gene, and drive cancer forward. The alterations were also scattered across the length of the gene in a pattern typically seen when another type of cancer-causing gene, known as tumor suppressors, are turned off.

“The pattern of mutations here looks a lot more like a tumor suppressor gene, but from the functional experiments, it behaved more like an oncogene,” Berger said.

When PREX2 functions normally, it interacts with the protein PTEN. PTEN is well known as a tumor suppressor, controlling growth in normal cells. Mouse experiments in Chin’s lab at Dana-Farber showed that PREX2 mutations spurred tumor growth in ways that are not fully understood.

“We still can’t say we know exactly how it works,” Garraway said. “PREX2 may be in a very interesting new category of mutated cancer genes that point us to at least one and maybe more pathways that would be worth targeting therapeutically in melanoma.”

The identification of PREX2 may be the tip of the iceberg.

“New melanoma genes remain to be discovered by this unbiased approach, as illustrated by the discovery of PREX2 and the demonstration of its oncogenicity in vivo,” said Chin.

Other Broad, Dana-Farber, and Harvard researchers who contributed to this work include Eran Hodis, Timothy P. Heffernan, Yonathan Lissanu Deribe, Michael S. Lawrence, Alexei Protopopov, Elena Ivanova, Ian R. Watson, Elizabeth Nickerson, Papia Ghosh, Hailei Zhang, Rhamy Zeid, Xiaojia Ren, Kristian Cibulskis, Andrey Y. Sivachenko, Nikhil Wagle, Carrie Sougnez, Robert Onofrio, Lauren Ambrogio, Daniel Auclair, Timothy Fennell, Scott L. Carter, Yotam Drier, Petar Stojanov, Meredith A. Singer, Douglas Voet, Rui Jing, Gordon Saksena, Jordi Barretina, Alex H. Ramos, Trevor J. Pugh, Nicolas Stransky, Melissa Parkin, Wendy Winckler, Scott Mahan, Kristin Ardlie, Jennifer Baldwin, Jennifer Wargo, Matthew Meyerson, Stacey B. Gabriel, Todd R. Golub, Eric S. Lander, and Gad Getz. Researchers from University Hospital Essen, Weizmann Institute of Science, and Medical University of Vienna also contributed to the work.

The work was supported by the National Human Genome Research Institute, National Cancer Institute, the Starr Cancer Consortium, FWF-Austrian Science Fund, NIH Director’s New Innovator Award, and the Burroughs-Wellcome Fund.

About the Broad Institute of Harvard and MIT

The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.

About Dana-Farber Cancer Institute

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Children’s Hospital Boston as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

