Fusions involving protein kinase C and membrane-associated proteins in benign fibrous histiocytoma.
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.
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Anna
A
Płaszczyca
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Jenny
J
Nilsson
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Linda
L
Magnusson
Department of Orthopedics, Karolinska University Hospital, SE-171 76 Solna, Sweden.
Otte
O
Brosjö
Department of Pathology, Karolinska University Hospital, SE-171 76 Solna, Sweden.
Olle
O
Larsson
Department of Orthopedics, Skåne University Hospital, Lund University, SE-221 85 Lund, Sweden.
Fredrik
F
Vult von Steyern
Department of Pathology, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Henryk A
HA
Domanski
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Henrik
H
Lilljebjörn
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Thoas
T
Fioretos
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Johnbosco
J
Tayebwa
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Nils
N
Mandahl
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden.
Karolin H
KH
Nord
Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden. Electronic address: fredrik.mertens@med.lu.se.
Fredrik
F
Mertens
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification; D002871:Chromosome Banding; D011992:Endosomes / Q000235:genetics / Q000473:pathology; D005260:Female; D018219:Histiocytoma, Benign Fibrous / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000302:isolation & purification; D008565:Membrane Proteins / Q000235:genetics* / Q000302:isolation & purification; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D064546:Protein Kinase C beta / Q000235:genetics* / Q000302:isolation & purification; D051745:Protein Kinase C-delta / Q000235:genetics* / Q000302:isolation & purification; D015398:Signal Transduction; D060149:Tetraspanin 30 / Q000235:genetics / Q000302:isolation & purification; D000098853:Podoplanin
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D015514:Oncogene Proteins, Fusion; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta; D060149:Tetraspanin 30; C554586:CD63 protein, human; C544374:LAMTOR1 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin; C579054:PRKCB protein, human; C497258:PRKCD protein, human
CD63; Cell membrane; Endosomes; Gene fusion; LAMTOR1; Podoplanin