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

Author:
  • Anna Płaszczyca
  • Jenny Nilsson
  • Linda Magnusson
  • Otte Brosjö
  • Olle Larsson
  • Fredrik Vult von Steyern
  • Henryk Domanski
  • Henrik Lilljebjörn
  • Thoas Fioretos
  • Johnbosco Tayebwa
  • Nils Mandahl
  • Karolin Hansén Nord
  • Fredrik Mertens
Publishing year: 2014
Language: English
Pages: 475-481
Publication/Series: International Journal of Biochemistry & Cell Biology
Volume: 53
Issue: Apr 8
Document type: Journal article
Publisher: Elsevier

Abstract english

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

  • Orthopedics
  • Cancer and Oncology
  • Medical Genetics

Other

Published
  • ISSN: 1878-5875
Thoas Fioretos
E-mail: thoas [dot] fioretos [at] med [dot] lu [dot] se

Principal investigator

Translational Genomic and Functional Studies of Leucemia

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66

Professor

Division of Clinical Genetics

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66

Professor

Translational Genomic and Functional Studies of Leucemia

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66