Novel LRRFIP2‐RAF1 fusion identified in an acral melanoma: A review of the literature on melanocytic proliferations with RAF1 fusions and the potential therapeutic implications

Abstract

A small subset of cutaneous melanomas harbor oncogenic gene fusions, which could potentially serve as therapeutic targets for patients with advanced disease as novel therapies are developed. Fusions involving RAF1 are exceedingly rare in melanocytic neoplasms, occurring in less than 1% of melanomas, and usually arise in tumors that are wild type for BRAF, NRAS, and NF1. We describe herein a case of acral melanoma with two satellite metastases and sentinel lymph node involvement. The melanoma had a concomitant KIT variant and LRRFIP2-RAF1 fusion. This constellation of molecular findings has not been reported previously in melanoma. We review the existing literature on melanocytic neoplasms with RAF1 fusions and discuss the potential clinical implications of this genetic event.

RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma‐like mesenchymal tumors

“…BRAF gene fusions have also been reported in multiple tumor types [41]. In striking contrast, RAF1 gene mutations have only rarely been reported as somatic events in cancer, although gene rearrangements involving different partners have been documented as oncogenic drivers [11–18,32–36]. In line with a previous case report [12], our data establish a driver role of aberrantly upregulated RAF1 function in this still poorly characterized subtype of pediatric spindle cell tumors.…”

“…This chimeric protein had been reported as a driver event in melanoma, breast carcinoma, and prostate cancer [29][30][31][32]. The second in-frame fusion involved LRRFIP2 (exons 1-12; NM_006309.4, ENST00000354379.8) and RAF1 (exons 8-17; NM_002880.4, ENST00000251849.9) (breakpoints: chr3:37055086 and chr3:12600415 for LRRFIP2 and RAF1, respectively), and had previously been reported in melanoma [33]. The third rearrangement was a novel gene fusion, CLIP1:: RAF1, involving exon 15 of CLIP1 (NM_001247997.2, ENST00000537178.5) and exon 8 of RAF1 (NM_002880.4, ENST00000251849.9) (breakpoints: chr12:122812494 and chr3:12600415 for CLIP1 and RAF1, respectively).…”

Sustained Response to the Mitogen-Activated Extracellular Kinase Inhibitor Trametinib in a Spindle Cell Sarcoma Harboring a QKI-RAF1 Gene Fusion

“…For example, patients with melanoma characterized by wildtype BRAF but harboring an RAF1 gene fusion responded to trametinib and cobimetinib. [10][11][12][13] There is also a report of an anaplastic pleomorphic xanthoastrocytoma harboring an ATG7-RAF1 gene fusion that responded to the MEK inhibitor cobimetinib. 4 The fusion partner of RAF1 in our case is QKI.…”

RASGRF1-rearranged Cutaneous Melanocytic Neoplasms With Spitzoid Cytomorphology

“…35,36 EWSR1, TRIM11, and MITF do not code for kinase proteins, and the cytomorphology of these tumors is not spitzoid. Many other kinase gene fusions have also been reported in non-Spitz melanocytic tumors, such as PRKCA and PKN1 fusions in pigmented epithelioid melanocytomas, [37][38][39] RAF1 fusions in a malignant melanoma arising in giant congenital melanocytic nevus, 40 an acral melanoma, 41 and a BAP1-inactivated melanocytic tumor associated with a congenital melanocytic nevus, 42 and BRAF fusions occurring in giant congenital melanocytic nevi 43,44 and malignant melanomas. 45 Besides the RAFGRF1 fusion, the RNA sequencing data identified several other mutations in the 3 cases, most of which were either indexed as "unreferenced" or "conflicting interpretations of pathogenicity," according to ClinVar.…”