Genomic landscape of malignant peripheral nerve sheath tumor (MPNST)-like melanoma.

Abstract

e22072 Background: Malignant Peripheral Nerve Sheath Tumor (MPNST)-like melanoma is a rare entity wherein cutaneous melanoma mimics histomorphological features of MPNST. The genomic landscape of MPNST-like melanoma has not been previously described. We report the genomic findings of 6 patients diagnosed with MPNST-like melanoma. Methods: We identified consecutive patients with confirmed histological diagnosis of MPNST-like melanoma. Archival tissue was submitted for whole exome and transcriptome sequencing analysis and genomic findings were compared to publicly available data on the genomic landscape of both melanoma and limited genetic descriptions of MPNST. Results: Six patients diagnosed with MPNST-like melanoma between November 2002 and July 2018 had archival tissue available (8 samples). Mean age at diagnosis was 60.5 years (38-74). The mean tumor mutational burden (TMB) was 35.72 mutations/exon coding megabase, ranging from 4.27 to 86.36. NF1 alterations were found in 4 (67%) of cases: one had 3 truncating mutations (W696 + X1870_splice + R1590C) associated with NF1 amplification, one had a deep deletion and another two had truncating mutations (I1908L and W696 + A1530V). Two tumors had non-V600 BRAF mutations that predict alteration in kinase function. We observed deletions of cell cycle regulators: CDKN2A and CDKN2B in 33%; and ZNF331 (19q13.42) in 83% of cases. SERPINB4 (18q21.3), described previously as a tumor suppressor in oral squamous cell carcinomas, was deleted in all samples. The patient with NF1 amplification and truncating mutations received immunotherapy due to metastatic disease and achieved a complete response; his tumor had a TMB of 72.6. Another patient who died of metastatic melanoma, treated with chemotherapy in the pre-immunotherapy era, lacked any NF1 mutation but had a Q61K NRAS mutation; the tumor had a TMB of 15. The remaining patients were treated with surgical resection alone and continue on follow-up. Conclusions: MPNST-like melanoma shares some frequently altered genes in cutaneous melanoma but possesses an excess of NF-1 mutations or deletions, in keeping with its neural-like phenotype. The high frequency of SERPINB4 alterations suggests a critical tumor suppressor role in this subtype of melanoma, warranting further investigation. Additionally, cell cycle dysregulation caused by deletion of ZNF331 and CDKN2A/B may be important in MPNST-like melanoma carcinogenesis.