Whole‐exome sequencing of oral mucosal melanoma reveals mutational profile and therapeutic targets

Abstract

Oral mucosal melanoma (OMM) is a rare and aggressive subtype of melanoma with little known about its pathogenesis or carcinogenesis. We therefore performed whole-exome sequencing (WES) on 19 matched OMM tumor/normal pairs in order to gain insight into potential genetic drivers of tumor formation. For the first time, we describe the comprehensive mutational profile of OMM. Our data suggest that the genetic background of OMM differs from those of other melanoma subtypes. We identified recurrent mutations involving KIT, POLE, PTPRD, PTCHD2, and DMXL2. Notably, copy number analysis revealed recurrently amplified regions of 12q14 (57.9%, containing CDK4) and 5p15 (47.4%, containing TERT). CNV analysis in a separate cohort of 15 samples validated the frequent CNV in CDK4 and TERT. We also observed that the melanocyte development and pigmentation signaling pathway is frequently altered in OMM. Furthermore, our data suggest several altered genes that may be amenable for targeted therapy. We identified one patient with metastatic OMM in our cohort who was identified to harbor a targetable KIT mutation using our WES results. This patient was able to achieve complete remission following implementation of KIT-targeted therapy. These findings provide further insight into the genetic underpinnings of OMM development and suggest that patients with OMM may benefit from WES analysis to identify potential targetable genetic mutations. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Array Comparative Genomic Hybridization Analysis Reveals Significantly Enriched Pathways in Canine Oral Melanoma

“…22 (8,24,27,28) together with a sigmoidal trend (a complex alternation of copy number gains followed immediately by copy number losses), in CFA 10 and 30 (8,24,28). In this study, CFA 10 and CFA 30 also showed the sigmoidal trend, and 7 of the regions found imbalanced were already reported in recent literature (Tables 2A,C) (24); with an § the syntenic regions reported by Curtin et al (5); no regions were shared with Lyu et al (7).…”

“…Large chromosomal aberrations, known to be deeply involved in solid tumors development (9), were investigated in hMMs through numerous techniques. Up to date, promising recurrent regions of gains and losses were identified (5) and confirmed by several investigations (4,7,8), in particular amplified portions of HSA 12q and 5p, which encode for genes as CDK4 and TERT, respectively (7). In addition, CCND1, KIT, and VEGFRA were proposed by a recent review (10) as targets for future investigations.…”

“…In summary, the genome coordinates of the 180.000 60-mer probes of each array were mapped firstly to the canine reference genome CanFam3.1, and then to the human reference genome GRCh38/hg38. The syntenic human regions were then compared with published data (5,7,8,24), to detect those regions shared by both hMMs and COMs. A comparative analysis between data produced herein, and recently published studies regarding the detection of CNAs in the canine genome through several techniques (as WES, WGS, aCGH, and FISH) (8,24,27,28), was also performed.…”

“…Orthologous chromosomal regions in canine and human genome were examined to assess conserved CNAs between COMs and hMMs. In human literature, frequent gains of regions of human chromosomes HSA 1, 4, 5, 6, 7, 8, 11, 12, 17, 20, and losses of regions of HSA 3, 4, 6, 8, 9, 10, 11, 17, 21, have been reported (5,7). The comparative analysis revealed 32 regions shared between COMs and hMMs, and regarded gains on CFA 9, 10, and 13, orthologous to HSA 17, 12, and 8-4 (respectively), and losses on CFA 11, 22 and 30, orthologous to HSA 9, 13, and 15 (respectively).…”

“…Human melanomas of mucosal sites (human Mucosal Melanoma, hMM) are neoplastic diseases of neuroectodermal origin, arising from non-cutaneous melanocytes migrated from the neural crest during embryogenesis (1)(2)(3)(4). Although still not fully characterized, hMMs show to rely on numerous copy number changes and whole chromosomes gains or losses, rather than on single-nucleotide mutations, and they lack the typical UV-signature of the cutaneous malignant melanomas (cMM) (4)(5)(6)(7)(8). Large chromosomal aberrations, known to be deeply involved in solid tumors development (9), were investigated in hMMs through numerous techniques.…”