BCAT1 and miR-2504: novel methylome signature distinguishes spindle/desmoplastic melanoma from superficial malignant peripheral nerve sheath tumor

Mod Pathol. 2019 Mar;32(3):338-345. doi: 10.1038/s41379-018-0146-z. Epub 2018 Oct 11.

Abstract

Superficial/cutaneous malignant peripheral nerve sheath tumor is a rare soft tissue neoplasm that shares morphological, immunohistochemical, and molecular features with spindle/desmoplastic melanoma. We aimed to identify a methylome signature to distinguish these two entities. We analyzed 15 cases of spindle/desmoplastic melanoma and 15 cases of cutaneous malignant peripheral nerve sheath tumor in 23 men and 7 women. DNA from formalin-fixed, paraffin-embedded tissues was extracted and processed using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. Using a home-grown informatics pipeline, we identified differentially methylated positions between the two entities. Functional network analysis for enrichment signatures was performed using DAVID tools. Identified differentially methylated positions were compared with the Cancer Genome Atlas's cutaneous melanoma dataset and a recently published malignant peripheral nerve sheath tumor dataset to assess the specificity of the identified signature. Unsupervised hierarchical clustering showed different patterns of methylation in cutaneous malignant peripheral nerve sheath tumor and spindle/desmoplastic melanoma. Two probes, cg20783223 and cg13332552, colocalized in the promoter region of BCAT1 and miR-2504. Pathway analysis highlighted enrichment in a subset of genes involved in breast and gastric cancer centered on BCAT1 and downstream activated genes in the mTOR pathway. Our study identifies BCAT1 as a novel methylome signature distinguishing spindle/desmoplastic melanoma from cutaneous malignant peripheral nerve sheath tumor.

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • DNA Methylation
  • Diagnosis, Differential
  • Female
  • Humans
  • Male
  • Melanoma / diagnosis
  • Melanoma / genetics*
  • Melanoma, Cutaneous Malignant
  • MicroRNAs / genetics*
  • Middle Aged
  • Neurofibrosarcoma / diagnosis
  • Neurofibrosarcoma / genetics*
  • Skin Neoplasms / diagnosis
  • Skin Neoplasms / genetics*
  • Soft Tissue Neoplasms / diagnosis
  • Soft Tissue Neoplasms / genetics*
  • Transaminases / genetics*
  • Young Adult

Substances

  • Biomarkers, Tumor
  • MIRN2504 microRNA, human
  • MicroRNAs
  • BCAT1 protein, human
  • Transaminases