Abstract

Background: Genomic alterations in melanoma often result in MAP-kinase (MAPK) activation, and include missense mutations and amplifications in RAS oncogenes (NRAS, KRAS, and HRAS). Colon cancer and overgrowth syndromes have been found to harbor rare internal tandem duplications (ITDs) in the switch II domain of RAS, which were recently biochemically validated to activate MAPK. Here, we investigated melanomas with RAS ITDs. Methods: Archived melanomas with comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform (FoundationOne®CDx) were queried for RAS alterations. Clinical and histopathologic data were reviewed. Results: From a cohort of 9,945 melanomas, 17 cases (0.2%) featured RAS indels in the switch II domain (10 KRAS, 6 NRAS, 1 HRAS), of which 15 were ITDs (n=7) or near ITDs (within one codon, n=8), with the duplication size from 6-10 amino acids. The median age was 62 years, with 53% males, and consisted of 7 primary tumors and 10 metastases. 13 cases were cutaneous primary, while 4 cases were mucosal primary (2 anorectal, 2 vulvar). Melanomas showed variable architectures, including wedge-shaped and nodular growth patterns. Cytomorphology was predominantly epithelioid, with a single vulvar melanoma comprised of spindle cells. Recurrent RAS indels included KRAS E63delinsKYSAMRDQ (n=3 cases), KRAS Y64_S65insNAMRDQY (n=2), NRAS M67_G75dup (n=2). 88% (n = 15) were wild-type for BRAF, NRAS, and NF1 genomic alterations (triple wild-type). Activating RAS ITDs were present in 0.6% of triple wild-type melanomas overall (15/2449). In melanomas with activating RAS ITDs, frequently mutated genes included TERTp (71%), CDKN2A (29%), CTNNB1 (18%), TP53 (12%), and PTEN (12%). Conclusions: Activating RAS ITDs characterize a significant novel subset of triple wild-type melanoma (0.6%) with frequent accompanying mutations in TERTp and CDKN2A. CGP of melanomas may improve tumor classification and guide directed therapeutic options.

Financial Disclosure:
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