Mutational Hotspot of TET2, IDH1, IDH2, SRSF2, SF3B1, KRAS, and NRAS from Human Systemic Mastocytosis Are Not Conserved in Canine Mast Cell Tumors

PLoS One. 2015 Nov 12;10(11):e0142450. doi: 10.1371/journal.pone.0142450. eCollection 2015.

Abstract

Introduction: Both canine cutaneous mast cell tumor (MCT) and human systemic mastocytosis (SM) are characterized by abnormal proliferation and accumulation of mast cells in tissues and, frequently, by the presence of activating mutations in the receptor tyrosine kinase V-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (c-KIT), albeit at different incidence (>80% in SM and 10-30% in MCT). In the last few years, it has been discovered that additional mutations in other genes belonging to the methylation system, the splicing machinery and cell signaling, contribute, with c-KIT, to SM pathogenesis and/or phenotype. In the present study, the mutational profile of the Tet methylcytosine dioxygenase 2 (TET2), the isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2), the serine/arginine-rich splicing factor 2 (SRSF2), the splicing factor 3b subunit 1 (SF3B1), the Kirsten rat sarcoma viral oncogene homolog (KRAS) and the neuroblastoma RAS viral oncogene homolog (NRAS), commonly mutated in human myeloid malignancies and mastocytosis, was investigated in canine MCTs.

Methods: Using the Sanger sequencing method, a cohort of 75 DNA samples extracted from MCT biopsies already investigated for c-KIT mutations were screened for the "human-like" hot spot mutations of listed genes.

Results: No mutations were ever identified except for TET2 even if with low frequency (2.7%). In contrast to what is observed in human TET2 no frame-shift mutations were found in MCT samples.

Conclusion: Results obtained in this preliminary study are suggestive of a substantial difference between human SM and canine MCT if we consider some target genes known to be involved in the pathogenesis of human SM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • DNA-Binding Proteins / genetics
  • Dioxygenases
  • Dog Diseases / genetics*
  • Dogs
  • GTP Phosphohydrolases / genetics
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Mast Cells / metabolism
  • Mast Cells / pathology
  • Mastocytosis, Systemic / genetics*
  • Membrane Proteins / genetics
  • Molecular Sequence Data
  • Mutation*
  • Nuclear Proteins / genetics
  • Phosphoproteins / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear / genetics
  • Ribonucleoproteins / genetics
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Serine-Arginine Splicing Factors

Substances

  • DNA-Binding Proteins
  • KRAS protein, human
  • Membrane Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear
  • Ribonucleoproteins
  • SF3B1 protein, human
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors
  • IDH2 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Dioxygenases
  • TET2 protein, human
  • GTP Phosphohydrolases
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)

Grants and funding

Dr. Zorzan’s PhD fellowship was provided by the Università degli Studi di Padova, Italy.