DNA methylation-based classification of sinonasal undifferentiated carcinoma

Mod Pathol. 2019 Oct;32(10):1447-1459. doi: 10.1038/s41379-019-0285-x. Epub 2019 Jun 11.

Abstract

Sinonasal undifferentiated carcinoma (SNUC) is an aggressive malignancy harboring IDH2 R172 mutations in >80% cases. We explored the potential of genome-wide DNA methylation profiling to elucidate tumor biology and improve the diagnosis of sinonasal undifferentiated carcinoma and its histologic mimics. Forty-two cases, including sinonasal undifferentiated, large cell neuroendocrine, small cell neuroendocrine, and SMARCB1-deficient carcinomas and olfactory neuroblastoma, were profiled by Illumina Infinium Methylation EPIC array interrogating >850,000 CpG sites. The data were analyzed using a custom bioinformatics pipeline. IDH2 mutation status was determined by the targeted exome sequencing (MSK-IMPACTTM) in most cases. H3K27 methylation level was assessed by the immunohistochemistry-based H-score. DNA methylation-based semi-supervised hierarchical clustering analysis segregated IDH2 mutants, mostly sinonasal undifferentiated (n = 10) and large cell neuroendocrine carcinomas (n = 4), from other sinonasal tumors, and formed a single cluster irrespective of the histologic type. t-distributed stochastic neighbor embedding dimensionality reduction analysis showed no overlap between IDH2 mutants, SMARCB1-deficient carcinoma and olfactory neuroblastoma. IDH2 mutants demonstrated a global methylation phenotype and an increase in repressive trimethylation of H3K27 in comparison to IDH2 wild-type tumors (p < 0.001). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed no difference in pathway activation between IDH2-mutated sinonasal undifferentiated and large cell neuroendocrine carcinomas. In comparison to SMARCB1-deficient, IDH2-mutated carcinomas were associated with better disease-free survival (p = 0.034) and lower propensity for lung metastasis (p = 0.002). ARID1A mutations were common in small cell neuroendocrine carcinoma but not among IDH2 mutants (3/3 versus 0/18 and p < 0.001). IDH2 mutations in sinonasal carcinomas induce a hypermethylator phenotype and define a molecular subgroup of tumors arising in this location. IDH2-mutated sinonasal undifferentiated carcinoma and large cell neuroendocrine carcinoma likely represent a phenotypic spectrum of the same entity, which is distinct from small cell neuroendocrine and SMARCB1-deficient sinonasal carcinomas. DNA methylation-based analysis of the sinonasal tumors has potential to improve the diagnostic accuracy and classification of tumors arising in this location.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma / diagnosis*
  • Carcinoma / genetics
  • Carcinoma / pathology
  • Carcinoma, Neuroendocrine / diagnosis
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / pathology
  • Carcinoma, Small Cell / diagnosis
  • Carcinoma, Small Cell / genetics
  • Carcinoma, Small Cell / pathology
  • DNA Methylation*
  • Female
  • Humans
  • Immunohistochemistry
  • Isocitrate Dehydrogenase / genetics*
  • Male
  • Maxillary Sinus Neoplasms / diagnosis*
  • Maxillary Sinus Neoplasms / genetics
  • Maxillary Sinus Neoplasms / pathology
  • Middle Aged
  • Mutation
  • SMARCB1 Protein / genetics*
  • Young Adult

Substances

  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Isocitrate Dehydrogenase

Supplementary concepts

  • Sinonasal undifferentiated carcinoma