Melanomas with activating RAF1 fusions: clinical, histopathologic, and molecular profiles

Erik A Williams,Julie Y Tse,Meagan Montesion,Nikunj Shah,Mark C Mochel,Jeff M Venstrom,Julia A Elvin,Brian M Alexander,Ethan S Sokol,Jeffrey S Ross,Radwa Sharaf,Dean C Pavlick

doi:10.1038/s41379-020-0510-7

Erik A Williams, Julie Y Tse + Show 10 more

Open Access

https://doi.org/10.1038/s41379-020-0510-7

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Abstract

A subset of melanomas is characterized by fusions involving genes that encode kinases. Melanomas with RAF1 fusions have been rarely reported, mostly in clinical literature. To investigate this distinctive group of melanomas, we searched for melanomas with activating structural variants in RAF1, utilizing our case archive of clinical samples with comprehensive genomic profiling (CGP) by a hybrid capture-based DNA sequencing platform. Clinical data, pathology reports, and histopathology were reviewed for each case. RAF1 breakpoints, fusion partners, and co-occurring genetic alterations were characterized. From a cohort of 7119 melanomas, 40 cases (0.6%) featured fusions that created activating structural variants in RAF1. Cases with activating RAF1 fusions had median age of 62 years, were 58% male, and consisted of 9 primary tumors and 31 metastases. Thirty-nine cases were cutaneous primary, while one case was mucosal (anal) primary. Primary cutaneous melanomas showed variable architectures, including wedge-shaped and nodular growth patterns. Cytomorphology was predominantly epithelioid, with only one case, a desmoplastic melanoma, consisting predominantly of spindle cells. RAF1 5′ rearrangement partners were predominantly intrachromosomal (n = 18), and recurrent partners included MAP4 (n = 3), CTNNA1 (n = 2), LRCH3 (n = 2), GOLGA4 (n = 2), CTDSPL (n = 2), and PRKAR2A (n = 2), all 5′ of the region encoding the kinase domain. RAF1 breakpoints occurred in intron 7 (n = 32), intron 9 (n = 4), intron 5 (n = 2), and intron 6 (n = 2). Ninety-eight percent (n = 39) were wild type for BRAF, NRAS, and NF1 genomic alterations (triple wild type). Activating RAF1 fusions were present in 2.1% of triple wild-type melanomas overall (39/1882). In melanomas with activating RAF1 fusions, frequently mutated genes included TERTp (62%), CDKN2A (60%), TP53 (13%), ARID2 (10%), and PTEN (10%). Activating RAF1 fusions characterize a significant subset of triple wild-type melanoma (2.1%) with frequent accompanying mutations in TERTp and CDKN2A. CGP of melanomas may improve tumor classification and inform potential therapeutic options, such as consideration of specific kinase inhibitors.

Highlights

The majority of melanomas harbor point mutations of BRAF, NRAS, KIT, or NF1 that drive tumor growth [1, 2]
Thirty-nine cases were consistent with either primary cutaneous melanoma or metastatic melanoma from a skin primary, while one case was a primary melanoma of anal mucosa
This study represents the first series of activating RAF1-fusion melanomas with clinicopathologic correlation and detailed characterization of genetic alterations

Summary

Introduction

The majority of melanomas harbor point mutations of BRAF, NRAS, KIT, or NF1 that drive tumor growth [1, 2]. Less common, represent the oncogenic drivers in emerging subgroups of melanoma, often through activation of MAP kinase pathways. Despite the central role of RAF1 in the MAP kinase pathway, there are only isolated reports of RAF1 (CRAF) fusions in melanomas, and the histopathologic characterizations of these tumors have been limited [6,7,8]. As specified in the most recent World Health Organization (WHO) classification [12], the term “Spitz melanoma” refers to melanoma with both histologic changes reminiscent of Spitz nevi and a known oncogenic fusion driver, of kinase-encoding genes. “spitzoid melanoma” refers to melanoma with some morphologic resemblance to Spitz nevus, but without a known fusion driver

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