Atypical BRAF and NRAS Mutations in Mucosal Melanoma

Abstract

Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with BRAF and NRAS mutations. We show that in addition to being less frequent, BRAF and NRAS mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the BRAF and NRAS mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical BRAF and NRAS mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.

Emerging strategies to treat rare and intractable subtypes of melanoma

“…Approximately 7%-22% of MMs have v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) somatic mutations or amplifications (Dumaz et al, 2019;Tyrrell & Payne, 2018). MMs located in the genital area appear to be driven by mutations in SF3B1 which encodes the subunit 1 of splicing factor 3b, a component of the spliceosome that processes pre-mRNA into mature transcripts (Furney et al, 2013;Oiso, Sakai, Yanagihara, Nishio, & Kawada, 2018;Quek et al, 2019).…”

“…Mucosal melanoma (MM) is one of the rarest types of melanoma, accounting for only 1% of all cases (Dumaz et al., 2019; McLaughlin et al., 2005), and has a significantly worse prognosis relative to the other subtypes (Dumaz et al., 2019). Distinct from cutaneous melanoma, MM arises from melanocytes located in mucosal membranes inside the body (i.e., genitourinary, anorectal, nasopharyngeal; Dumaz et al., 2019). The head and neck (55), vulva (18), and anus (24) are the most common observed sites; however, MM can also occur in the gut, lungs, and urinary track (Figure 2; Chang, Karnell, & Menck, 1998).…”

Uncommon Subtypes of Malignant Melanomas: A Review Based on Clinical and Molecular Perspectives

“…BRAF mutations are present in MM but at a lower frequency (6–12%) compared to CM [ 113 , 114 , 115 ]. In a whole-genome sequencing analysis of 67 MM samples performed by Newell et al, BRAF mutations were most commonly found in the protein tyrosine kinase domain, with V600E, V600K, and V600R being the most common BRAF mutations [ 116 ].…”

“…On the other hand, non-V600 mutations appear to be present in a higher proportion in MM. In this context, a compiled BRAF mutation analysis of 1339 MM performed by Dumaz et al showed that 37% of mutations were placed on another codon different from V600, particularly on D594 (40%), G469 (24%), and K601 (16%) [ 113 ].…”

“…The NRAS mutation rate is estimated to be around 8% [ 115 ]. The most frequent locations affected are similar in both CM and MM (Q61, G12, and G13) [ 113 ]. NRAS Q61 mutations occur at a lower rate in this population, which may be explained by the association between this particular mutation and UV exposure.…”