Abstract
The largest and most comprehensive genomic profile of cutaneous melanomas suggests they fall into four categories characterized by different driver mutations. The three largest groups carry mutations in BRAF, RAS family genes, or NF1. A fourth group stands apart because it has none of those mutations.
A new, comprehensive genomic analysis suggests that cutaneous melanomas can be divided into four subtypes.
Doctors already rely on genomic information to choose treatments for melanoma. For the roughly 50% of patients who carry certain mutations in BRAF, three FDA-approved drugs can treat metastatic and inoperable tumors: vemurafenib (Zelboraf; Genentech), dabrafenib (Tafinlar; GlaxoSmithKline), and trametinib (Mekinist; GlaxoSmithKline). Although these treatments can dramatically shrink tumors, the benefits often don't last. Researchers hope that delving deeper into melanoma genomes will reveal mutations that suggest combination therapies or additional targets for drug development.
In the new study, a team of researchers with The Cancer Genome Atlas (TCGA) Network performed the largest, most extensive genomic analysis of melanoma to date. Of the 333 tumors from 331 patients with cutaneous melanoma included in the study, 20% were primary tumors and the rest were metastases. The scientists used whole-exome sequencing, DNA copy-number profiling, mRNA sequencing, DNA methylation profiling, miRNA sequencing, and protein expression profiling to assess the tumors.
The tumors were riddled with mutations, more than in any other cancer type profiled by TCGA researchers. To sort through them, the team applied two algorithms that identify driver mutations likely to be involved in tumor development and growth.
As the researchers reported last month in Cell, their analysis splits cutaneous melanomas into four groups based on the presence of the most prevalent driver mutations. One category contained the 47% of tumors with BRAF mutations. The second group, which encompassed 29% of the tumors, carried mutations in one of the RAS family genes, usually NRAS. NF1 was mutated in 9% of tumors. A final, catch-all group included the 15% of tumors that lacked mutations in all three of these genes. Previous studies had suggested the first two categories but not the last two, notes co-author Jeffrey Gershenwald, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Which category a tumor fell into didn't affect patients' survival. However, when the researchers analyzed gene expression, they found that patients with a better prognosis tended to show higher expression of immune system genes indicative of T-cell infiltration, such as LCK.
The study points to potential treatment options for tumors in each subgroup, including targeted and immune therapies. It suggests, for example, that MEK inhibitors such as trametinib, already used for patients with BRAF mutations, might benefit those with NF1 mutations. In addition, measuring LCK expression and testing for immune cells in tumors might help determine a patient's prognosis and identify individuals who could benefit from immunotherapies.
“This is a very solid foundation for the field, and it will give lots of resources for future clinical studies,” says Meenhard Herlyn, DVM, DSc, of the Wistar Institute in Philadelphia, PA, who wasn't connected to the study. What researchers need to do now, he says, is further analyze these categories to identify additional subgroups of melanomas that can be targeted by approved therapies or that could suggest avenues for drug development.
