Identification of recurrent mutational events in anorectal melanoma

Abstract

Anorectal melanoma is a rare disease that carries a poor prognosis. To date, limited genetic analyses confirmed KIT mutations as a recurrent genetic event similar to other mucosal melanomas, occurring in up to 30% of anorectal melanomas. Importantly, a subset of tumors harboring activating KIT mutations have been found to respond to c-Kit inhibitor-based therapy, with improved patient survival at advanced tumor stages. We performed comprehensive targeted exon sequencing analysis of 467 cancer-related genes in a larger series of 15 anorectal melanomas, focusing on potentially actionable variants based on gain- and loss-of-function mutations. We report the identification of oncogenic driver events in the majority (93%) of anorectal melanomas. These included variants in canonical MAPK pathway effectors rarely observed in cutaneous melanomas (including an HRAS mutation, as well as a BRAF mutation resulting in duplication of threonine 599), and recurrent mutations in the tumor suppressor NF1 in 20% of cases, which represented the second-most frequently mutated gene after KIT in our series. Furthermore, we identify SF3B1 mutations as a recurrent genetic event in mucosal melanomas. Our findings provide an insight into the genetic diversity of anorectal melanomas, and suggest significant potential for alternative targeted therapeutics in addition to c-Kit inhibitors for this melanoma subtype.

Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma

“…Mutations in BRAF were seen but these were not the driver V600 mutations described in cutaneous melanoma (Table 1). Similar to other studies 7, frequent mutations in KIT were found, especially in the vulvovaginal and anorectal subtypes. In these two groups of patients, the KIT mutations were comutated with NF1 in 32% of the samples.…”

“…The other two patients carried mutation R625C in SF3B1 , and one variant R625S. A recent targeted sequencing of 15 anorectal mucosal melanoma patients described five patients with the identical SF3B1 R625 mutation, confirming our findings 7. WES in cutaneous melanoma found only a very low frequency of SF3B1 R625H/C mutations, 2/231 cutaneous patient samples 14.…”

“…Discovery of these comutations could provide insight into the lack of response of mucosal melanoma to traditional melanoma treatments. Importantly, we discovered a recurrent R625 mutation in SF3B1 , in vulvovaginal melanomas that was previously only described in anorectal and ocular melanomas 6,7. We confirmed that SF3B1 -mutant samples have differential splicing of at least four genes found in previously described SF3B1 -mutant cancers 6,8.…”

“…This suggests that SF3B1 might be exploited as a novel prognostic and/or therapeutic target, specifically in mucosal melanomas for anorectal and vulvovaginal sites. Figure 4a illustrates the known SF3B1 mutations found in this study and other published cancer studies from cBioPortal 7,18. Both uveal melanoma and breast cancer harbor mutations in the HEAT domain of SF3B1 , with a majority of samples having mutations at positions R625 and K700, respectively (Fig.…”

“…We identified comutations of KIT and NF1 (32%), as well as recurrent SF3B1 mutations (42%). SF3B1 mutations have not been previously reported in vulvovaginal or nasopharyngeal mucosal melanoma, and only once previous study found mutations in anorectal mucosal melanoma using targeted sequencing 7. In addition, our report is the first study in demonstrating the functional role of SF3B1 R625 mutations inducing alternative splicing in mucosal melanoma.…”