Consistent copy number changes and recurrent PRKAR1A mutations distinguish melanotic schwannomas from melanomas: SNP-array and next generation sequencing analysis Journal Article


Authors: Wang, L.; Zehir, A.; Sadowska, J.; Zhou, N.; Rosenblum, M.; Busam, K.; Agaram, N.; Travis, W.; Arcila, M.; Dogan, S.; Berger, M. F.; Cheng, D. T.; Ladanyi, M.; Nafa, K.; Hameed, M.
Article Title: Consistent copy number changes and recurrent PRKAR1A mutations distinguish melanotic schwannomas from melanomas: SNP-array and next generation sequencing analysis
Abstract: Melanotic Schwannomas (MS) are rare tumors that share histological features with melanocytic tumors and schwannomas. However, their genetics are poorly understood. To elucidate the genetic characteristics of MS, we performed genome-wide studies in a series of cases. Twelve MS cases were available for the study. Genomic DNAs extracted from formalin-fixed paraffin embedded tumor tissues were subjected to copy number (CN) and allelic imbalance (AI) analysis by Single Nucleotide Polymorphism (SNP)-array and screened for mutations in coding exons of 341 key cancer-associated genes using a hybrid capture-based next-generation sequencing (NGS) assay. Sanger sequencing was used to further verify recurrent mutations detected by NGS study. SNP-array analysis revealed remarkably stereotypic chromosomal abnormalities in MS. Hypodiploidy was common, typically involving monosomies of chromosomes 1, 2, and 17. All 12 samples showed mutations in PRKAR1A gene, including 2 cases with 2 mutations each. The 14 mutations were scattered across PRKAR1A, and most were inactivating mutations. AI on 17q, presenting as loss of heterozygosity with or without CN losses, combined with a PRKAR1A mutation was observed in 9/12 MS cases. The remaining 3 cases included the two samples harboring two mutations in PRKAR1A. MS exhibits a stereotypic pattern of chromosomal losses. In contrast, melanomas are typically characterized by the presence of multiple CN aberrations, without demonstrable differences in the frequency of losses and gains. Inactivation of both alleles of PRKAR1A by "two hits" observed in almost all cases underscores the central role of PRKAR1A in the pathogenesis of this neoplasm. © 2015 Wiley Periodicals, Inc.
Keywords: adult; clinical article; aged; middle aged; young adult; gene sequence; single nucleotide polymorphism; exon; cancer patient; follow up; chromosome 1; melanoma; genetic association; mutator gene; chromosome aberration; heterozygosity loss; dna extraction; genetic code; chromosome 2; chromosome 17; genomic dna; formaldehyde; paraffin; neurilemoma; monosomy; hybrid; next generation sequencing; allelic imbalance; human; male; female; priority journal; article; melanotic schwannoma; prkar1a gene; stereotypy
Journal Title: Genes Chromosomes and Cancer
Volume: 54
Issue: 8
ISSN: 1045-2257
Publisher: Wiley Periodicals, Inc  
Date Published: 2015-08-01
Start Page: 463
End Page: 471
Language: English
DOI: 10.1002/gcc.22254
PROVIDER: scopus
PUBMED: 26031761
PMCID: PMC6446921
DOI/URL:
Notes: Export Date: 2 July 2015 -- Source: Scopus
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MSK Authors
  1. Meera Hameed
    213 Hameed
  2. Khedoudja Nafa
    222 Nafa
  3. Narasimhan P Agaram
    158 Agaram
  4. Marc Rosenblum
    380 Rosenblum
  5. Marc Ladanyi
    1190 Ladanyi
  6. William D Travis
    680 Travis
  7. Snjezana Dogan
    158 Dogan
  8. Lu Wang
    147 Wang
  9. Ahmet Zehir
    311 Zehir
  10. Michael Forman Berger
    602 Berger
  11. Maria Eugenia Arcila
    554 Arcila
  12. Klaus J Busam
    614 Busam
  13. Donavan Tai Suan Cheng
    51 Cheng
  14. Nengyi   Zhou
    7 Zhou