Genomic Classification of Cutaneous Melanoma

Abstract

SUMMARY We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multidimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

“…The majority of melanomas have an activated MAPK pathway, and recently, melanoma tumors were stratified into genomic subtypes according to mutations in the BRAF , RAS , or NF1 genes (Cancer Genome Atlas Network, 2015). Of the 870 cases examined, 452 (52%) had nonsynonymous mutations in BRAF , and of those, 408 cases (90%) had a recurrent hotspot mutation at the V600 or K601 residues (Fig.…”

“…The 870 cases were stratified according to the genomic subtypes described previously (Cancer Genome Atlas Network, 2015): the BRAF subtype ( n  = 404, 46%), the RAS subtype ( n  = 260, 30%), the NF1 subtype ( n  = 80, 9%), and the triple‐wild‐type subtype ( n  = 122, 14%) (Fig. 2C, Table 1).…”

“…The present study provides extensive characterization of genomic subtypes based on mutations in BRAF , RAS , and NF1 by using a large dataset comprising mutation data for 1461 genes in 864 clinically annotated melanomas. BRAF ‐subtype tumors were typically found in younger patients (Cancer Genome Atlas Network, 2015). These tumors were enriched in PTEN mutations, confirming frequent co‐occurrence of BRAF and PTEN mutations in melanoma, as shown previously (Jonsson et al ., 2007; Tsao et al ., 2012).…”

“…(2015). In all external studies, the somatic mutation data in MAF format were provided and were downloaded from the supplementary section of each of the publications (Hodis et al ., 2012; Krauthammer et al ., 2015), whereas for the TCGA project, automated somatic calls were downloaded for 472 melanoma tumors from the TCGA data portal (frozen March 14, 2016) (Cancer Genome Atlas Network, 2015). Oncotator was used to annotate the effect on the protein level for identified somatic mutations (https://confluence.broadinstitute.org/display/CGATools/Oncotator).…”

“…More recently, a framework for genomic classification of melanoma has been proposed by the Cancer Genome Atlas network (TCGA) (Cancer Genome Atlas Network, 2015). The four subtypes have been defined based on the mutational pattern in BRAF , RAS , NF1 , or none of these, the so‐called triple‐wild‐type group.…”