TCGA Classifies Four Melanoma Subtypes

New data out of the Cancer Genome Atlas (TCGA) suggests that cutaneous melanomas can be classified into four categories based on the pattern of the most prevalent significantly mutated genes: BRAF, RAS, NF1, and Triple-WT.

“Such a genomic classification provides a framework for exploring how additional molecular alterations may explain observed biological and clinical differences among the subtypes,” wrote Jeffrey E. Gershenwald, MD, professor of surgery at the University of Texas MD Anderson Cancer Center, and colleagues from TCGA in Cell. “It also provides signposts for identification of drugable targets and predictive biomarkers, as well as potentially useful guidance for decisions about therapy.”

Gershenwald and colleagues used DNA, RNA, and protein-based analysis to establish this genomic framework from 333 primary and/or metastatic melanomas taken from 331 patients. They matched these samples with peripheral blood from 331 adult patients.

Data showed that the largest genomic subtype was defined by the presence of BRAF hot-spot mutations, which 52% of cases harbored. The next most common subtypes were defined by the presence of RAS hot-spot mutations (28% of cases) and NF1 mutations (14% of cases). Finally, the researchers defined Triple-WT as the absence of hot-spot BRAF, RAS, or NF1 mutations.

The researchers noted that patients with BRAF mutations were younger than those in the other subtype groups, and patients with the NF1 subtype tended to be significantly older.

They also found that all four genomic subtypes shared common downstream signaling pathways, but their activation of these pathways differed.

“For example, BRAF and MEK inhibitor combinations are now used to treat patients with BRAF mutant melanomas, and MEK inhibitor combinations are being explored for RAS mutant melanomas,” said Ian Watson, PhD, instructor of genomic medicine at MD Anderson Cancer Center, in a prepared statement. “Pre-clinical studies have already demonstrated that some NF1 melanoma cell lines respond to MEK inhibitors, but more work is needed to identify responders and non-responders within this new melanoma subtype, as well as to determine strategies to treat Triple-WT melanoma patients.”

According to the researchers, there was no significant correlation between genomic classifications of melanoma and patient outcomes; however, they did note that “samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high [lymphocyte-specific protein tyrosine kinase] LCK protein expression, a T-cell marker, were associated with improved patient survival.”