title: Frequent low-level mutations of protein kinase D2 in angiolipoma.
abstract: Tumours displaying differentiation towards normal fat constitute the most common subgroup of soft tissue neoplasms. A series of such tumours was investigated by whole-exome sequencing followed by targeted ultra-deep sequencing. Eighty per cent of angiolipomas, but not any other tumour type, displayed mutations in the protein kinase D2 (PRKD2) gene, typically in the part encoding the catalytic domain. The absence of other aberrations at the chromosome or RNA level suggests that PRKD2 mutations are critical for angiolipoma development. Consistently, the mutated PRKD2 alleles were present at low (3-15%) frequencies, indicating that only a subset of the tumour cells is affected. Indeed, by sequencing mature fat cells and other cells separately, the former typically showed the highest mutation frequencies. Thus, we hypothesize that altered PRKD2 signalling in the adipocytic cells drives tumourigenesis and, in agreement with its pivotal role in angiogenesis, induces the vessel formation that is characteristic for angiolipoma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hofvander
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.
authors.forename: Elsa
authors.initials: E
authors.lastname: Arbajian
authors.affiliation: Department of Experimental Medical Science, Lund University, 221 84, Lund, Sweden.
authors.forename: Karin G
authors.initials: KG
authors.lastname: Stenkula
authors.affiliation: Department of Experimental Medical Science, Lund University, 221 84, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Lindkvist-Petersson
authors.affiliation: Science for Life Laboratory, Department of Physics, Chemistry and Biology, Linköping University, 581 83, Linköping, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Magnusson
authors.affiliation: Department of Orthopedics, Clinical Sciences, Lund University and Skåne University Hospital, 221 85, Lund, Sweden.
authors.forename: Fredrik Vult
authors.initials: FV
authors.lastname: von Steyern
authors.affiliation: Department of Pathology, Office for Medical Services, Division of Laboratory Medicine, 221 85, Lund, Sweden.
authors.forename: Pehr
authors.initials: P
authors.lastname: Rissler
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.|Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, 221 85, Lund, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
mesh_terms: D017667:Adipocytes; D000595:Amino Acid Sequence; D018206:Angiolipoma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D059472:Exome / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000235:genetics*; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology
chemical_list: D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human
keywords: PRKD2; deep sequencing; lipoma