Chromosomal translocations inactivating CDKN2A support a single path for malignant peripheral nerve sheath tumor

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Miriam Magallón-Lorenz1, Juana Fernández-Rodríguez2,3,4, Ernest Terribas1,5

  • 1Hereditary Cancer Group, Germans Trias i Pujol Research Institute (IGTP)-PMPPC, Badalona, 08916, Barcelona, Spain.

Human Genetics
|June 1, 2021
PubMed

Insights

Malignant peripheral nerve sheath tumors (MPNST) consistently inactivate the CDKN2A gene through translocations, deletions, or mutations. This discovery suggests a unified molecular pathway for MPNST development in both sporadic and neurofibromatosis type 1 cases.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with poor prognosis.
  • MPNSTs arise sporadically or in individuals with neurofibromatosis type 1 (NF1).
  • Loss of CDKN2A/B is a known early event, but its complete inactivation is not always observed, suggesting alternative MPNST initiation pathways.

Purpose of the Study:

  • To conduct a comprehensive genomic analysis of MPNST cell lines and tumors.
  • To investigate the status of CDKN2A inactivation in MPNST.
  • To determine if a single molecular pathway underlies MPNST initiation.

Main Methods:

  • Comprehensive genomic analysis of MPNST cell lines and primary tumors.
  • Analysis of CDKN2A deletions and point mutations.
  • Identification and validation of chromosomal translocations involving CDKN2A using PCR and Sanger sequencing.

Main Results:

  • A high frequency of chromosomal translocations involving CDKN2A was identified in MPNST cell lines and tumors.
  • Translocation breakpoints frequently clustered in a specific intronic hotspot region near CDKN2A exon 2.
  • Bi-allelic inactivation of CDKN2A was confirmed in all analyzed MPNST samples (15 tumors, 8 cell lines).

Conclusions:

  • The findings support a single, consistent molecular pathway for MPNST initiation, involving bi-allelic CDKN2A inactivation.
  • This unified pathway applies to both sporadic and NF1-related MPNSTs.
  • Understanding CDKN2A inactivation mechanisms has significant implications for MPNST diagnostics and therapeutic strategies.

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