NIH researchers survey landscape of melanoma genome

March 23, 2016

Next, the researchers looked for recurrent, or hot-spot, mutations that occurred in multiple patient tumors. The BRAF gene with a hotspot mutation previously implicated in melanoma led a list of nine additional genes with mutations that occurred in more than one tumor. Mutations in seven of the nine genes caused protein-coding changes. These seven hot-spot mutations led the researchers to look precisely for these mutations in 153 additional melanoma tumors.

Mutations in one particular gene, known as TRRAP, emerged as remarkable for occurring at the exact position in six separate individuals with melanoma. TRRAP harbors a recurrent mutation clustered in one position along the string of DNA code in about 4 percent of cases.

"These data suggest that TRRAP is a driver and probably an oncogene," said Dr. Samuels. Oncogenes are cancer-causing genes that enable the cell to survive despite stressful conditions, rather than die off normally. "This was one of the most important discoveries in the study since we never expected to identify novel hot-spot mutations," she said.

TRRAP is found in many species, suggesting its importance in normal function and that mutations in this gene would detrimentally affect protein function. To confirm a possible cell-survival function for TRRAP, the researchers disrupted the gene in mutant cell lines. The cells had an increase in cell death over time. Cancer cells normally fail to undergo cell death, which allows them to become immortal and cause disease. The test showed that TRRAP is a cancer-causing oncogene, because the mutant cell is clearly dependent on it. Dr. Samuels cautioned that while this discovery is exciting, it remains a basic science finding and does not necessarily suggest a therapy.

Lastly, the researchers used cell signaling pathway analysis, identifying glutamate signaling as a pathway involved in melanoma. "We are starting to explore what mutations do to the glutamate pathway," said Dr. Samuels, noting that ongoing research will entail complex biochemistry. She added that NIH colleagues published a study in the April 21, 2003, issue of Nature Genetics almost exactly eight years ago, implicating the glutamate signaling pathway in melanoma.

"This work demonstrates that our intramural researchers are on the front line of genomics and bioinformatics, providing high quality data and analysis to address important questions about health and disease," said NHGRI Scientific Director Daniel Kastner, M.D., Ph.D.

As part of their sequencing analysis, NISC investigators developed a statistical tool named Most Probable Genotype. The tool calculates reliability of data produced in the sequencing process. "This paper is not only about biology," said Dr. Samuels. "We are providing an effective tool for the other researchers who conduct exome sequencing so they too are able to validate which DNA alternations are reliably detected."

Source: NIH/National Human Genome Research Institute