title: Identification of Novel Fusion Genes in Testicular Germ Cell Tumors.
abstract: Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men ages 15 to 44 years. Embryonal carcinomas (EC) comprise a subset of TGCTs that exhibit pluripotent characteristics similar to embryonic stem (ES) cells, but the genetic drivers underlying malignant transformation of ECs are unknown. To elucidate the abnormal genetic events potentially contributing to TGCT malignancy, such as the existence of fusion genes or aberrant fusion transcript expression, we performed RNA sequencing of EC cell lines and their nonmalignant ES cell line counterparts. We identified eight novel fusion transcripts and one gene with alternative promoter usage, ETV6. Four out of nine transcripts were found recurrently expressed in an extended panel of primary TGCTs and additional EC cell lines, but not in normal parenchyma of the testis, implying tumor-specific expression. Two of the recurrent transcripts involved an intrachromosomal fusion between RCC1 and HENMT1 located 80 Mbp apart and an interchromosomal fusion between RCC1 and ABHD12B. RCC1-ABHD12B and the ETV6 transcript variant were found to be preferentially expressed in the more undifferentiated TGCT subtypes. In vitro differentiation of the NTERA2 EC cell line resulted in significantly reduced expression of both fusion transcripts involving RCC1 and the ETV6 transcript variant, indicating that they are markers of pluripotency in a malignant setting. In conclusion, we identified eight novel fusion transcripts that, to our knowledge, are the first fusion genes described in TGCT and may therefore potentially serve as genomic biomarkers of malignant progression.
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway. Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Hoff
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway. Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Sharmini
authors.initials: S
authors.lastname: Alagaratnam
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway. Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Sen
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway. Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Jarle
authors.initials: J
authors.lastname: Bruun
authors.affiliation: Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, United Kingdom. Centre for Stem Cell Biology, University of Sheffield, Western Bank, Sheffield, United Kingdom.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrews
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway. Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway. Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway. rolf.i.skotheim@rr-research.no.
authors.forename: Rolf I
authors.initials: RI
authors.lastname: Skotheim
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D050939:Gene Fusion; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger