Fusions involving protein kinase C and membrane-associated proteins in benign fibrous histiocytoma

Int J Biochem Cell Biol. 2014 Aug;53:475-81. doi: 10.1016/j.biocel.2014.03.027. Epub 2014 Apr 8.

Abstract

Benign fibrous histiocytoma (BFH) is a mesenchymal tumor that most often occurs in the skin (so-called dermatofibroma), but may also appear in soft tissues (so-called deep BFH) and in the skeleton (so-called non-ossifying fibroma). The origin of BFH is unknown, and it has been questioned whether it is a true neoplasm. Chromosome banding, fluorescence in situ hybridization, single nucleotide polymorphism arrays, RNA sequencing, RT-PCR and quantitative real-time PCR were used to search for recurrent somatic mutations in a series of BFH. BFHs were found to harbor recurrent fusions of genes encoding membrane-associated proteins (podoplanin, CD63 and LAMTOR1) with genes encoding protein kinase C (PKC) isoforms PRKCB and PRKCD. PKCs are serine-threonine kinases that through their many phosphorylation targets are implicated in a variety of cellular processes, as well as tumor development. When inactive, the amino-terminal, regulatory domain of PKCs suppresses the activity of their catalytic domain. Upon activation, which requires several steps, they typically translocate to cell membranes, where they interact with different signaling pathways. The detected PDPN-PRKCB, CD63-PRKCD and LAMTOR1-PRKCD gene fusions are all predicted to result in chimeric proteins consisting of the membrane-binding part of PDPN, CD63 or LAMTOR1 and the entire catalytic domain of the PKC. This novel pathogenetic mechanism should result in constitutive kinase activity at an ectopic location. The results show that BFH indeed is a true neoplasm, and that distorted PKC activity is essential for tumorigenesis. The findings also provide means to differentiate BFH from other skin and soft tissue tumors. This article is part of a Directed Issue entitled: Rare cancers.

Keywords: CD63; Cell membrane; Endosomes; Gene fusion; LAMTOR1; Podoplanin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Carrier Proteins / genetics
  • Carrier Proteins / isolation & purification
  • Chromosome Banding
  • Endosomes / genetics
  • Endosomes / pathology
  • Female
  • Histiocytoma, Benign Fibrous / genetics*
  • Histiocytoma, Benign Fibrous / pathology
  • Humans
  • In Situ Hybridization, Fluorescence
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / isolation & purification
  • Membrane Proteins / genetics*
  • Membrane Proteins / isolation & purification
  • Middle Aged
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / isolation & purification
  • Polymorphism, Single Nucleotide
  • Protein Kinase C beta / genetics*
  • Protein Kinase C beta / isolation & purification
  • Protein Kinase C-delta / genetics*
  • Protein Kinase C-delta / isolation & purification
  • Signal Transduction
  • Tetraspanin 30 / genetics
  • Tetraspanin 30 / isolation & purification

Substances

  • CD63 protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • LAMTOR1 protein, human
  • Membrane Glycoproteins
  • Membrane Proteins
  • Oncogene Proteins, Fusion
  • PDPN protein, human
  • Tetraspanin 30
  • PRKCB protein, human
  • PRKCD protein, human
  • Protein Kinase C beta
  • Protein Kinase C-delta