title: Activation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney.
abstract: Clear cell sarcoma of the kidney (CCSK) is a rare tumor type affecting infants and young children. Most CCSKs display few genomic aberrations, and no general underlying mechanism for tumor initiation has yet been identified, although a YWHAE-NUTM2B/NUTM2E fusion gene has been observed in a minority of cases. We performed RNA-sequencing of 22 CCSKs to investigate the presence of additional fusion transcripts. The presence of the YWHAE-NUTM2B/NUTM2E fusion was confirmed in two cases. In addition, a novel IRX2-TERT fusion transcript was identified in one case. SNP-array analyses revealed the underlying event to be an interstitial deletion in the short arm of chromosome 5 (5p15.33). TERT was dramatically upregulated under the influence of the IRX2 promoter. In line with TERT expression being driven by active IRX2 regulatory elements, we found a high expression of IRX2 in CCSKs irrespective of fusion gene status. IRX2 was also expressed in human fetal kidney - the presumed tissue of origin for CCSK. We conclude that in addition to promoter mutations and epigenetic events, TERT can also be activated in tumors via formation of fusion transcripts.
authors.affiliation: Department of Clinical Genetics, BMC C13, Lund University, Lund SE 221 84, Sweden. Electronic address: jenny.karlsson@med.lu.se.
authors.forename: Jenny
authors.initials: J
authors.lastname: Karlsson
authors.affiliation: Department of Clinical Genetics, BMC C13, Lund University, Lund SE 221 84, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Lilljebjörn
authors.affiliation: Department of Clinical Genetics, BMC C13, Lund University, Lund SE 221 84, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Holmquist Mengelbier
authors.affiliation: Department of Clinical Genetics, BMC C13, Lund University, Lund SE 221 84, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Valind
authors.affiliation: Department of Clinical Genetics, BMC C13, Lund University, Lund SE 221 84, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rissler
authors.affiliation: Department of Pediatric Oncology and hematology, Clinical Sciences, Lund University, Lund 221 85, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Øra
authors.affiliation: Department of Clinical Genetics, BMC C13, Lund University, Lund SE 221 84, Sweden.
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.affiliation: Department of Clinical Genetics, BMC C13, Lund University, Lund SE 221 84, Sweden; Department of Pathology, Skåne Regional and University Laboratories, Lund SE 221 85, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
mesh_terms: D000328:Adult; D001483:Base Sequence; D005333:Fetus / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D050596:Oncogene Fusion / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018227:Sarcoma, Clear Cell / Q000235:genetics*; D017423:Sequence Analysis, RNA; D019098:Telomerase / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C501595:IRX2 protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C509186:TERT protein, human; D019098:Telomerase
keywords: Fusion transcript; IRX2; Pediatric kidney tumors; RNA sequencing; TERT