title: Complex chromosomal rearrangements by single catastrophic pathogenesis in NUT midline carcinoma.
abstract: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare aggressive malignancy often occurring in the tissues of midline anatomical structures. Except for the pathognomonic BRD3/4-NUT rearrangement, the comprehensive landscape of genomic alterations in NMCs has been unexplored.
  
  
  
  We investigated three NMC cases, including two newly diagnosed NMC patients in Seoul National University Hospital, and a previously reported cell line (Ty-82). Whole-genome and transcriptome sequencing were carried out for these cases, and findings were validated by multiplex fluorescence in situ hybridization and using individual fluorescence probes.
  
  
  
  Here, we present the first integrative analysis of whole-genome sequencing, transcriptome sequencing and cytogenetic characterization of NUT midline carcinomas. By whole-genome sequencing, we identified a remarkably similar pattern of highly complex genomic rearrangements (previously denominated as chromoplexy) involving the BRD3/4-NUT oncogenic rearrangements in two newly diagnosed NMC cases. Transcriptome sequencing revealed that these complex rearrangements were transcribed as very simple BRD3/4-NUT fusion transcripts. In Ty-82 cells, we also identified a complex genomic rearrangement involving the BRD4-NUT rearrangement underlying the simple t(15;19) karyotype. Careful inspections of rearrangement breakpoints indicated that these rearrangements were likely attributable to single catastrophic events. Although the NMC genomes had >3000 somatic point mutations, canonical oncogenes or tumor suppressor genes were rarely affected, indicating that they were largely passenger events. Mutational signature analysis showed predominant molecular clock-like signatures in all three cases (accounting for 54%-75% of all base substitutions), suggesting that NMCs may arise from actively proliferating normal cells.
  
  
  
  Taken together, our findings suggest that a single catastrophic event in proliferating normal cells could be sufficient for neoplastic transformation into NMCs.
authors.affiliation: Korea Advanced Institute of Science and Technology, Graduate School of Medical Science and Engineering, Daejeon, South Korea.
authors.forename: J-K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Molecular Cytogenetics Core Facility, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Louzada
authors.affiliation: Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: An
authors.affiliation: Department of Laboratory Medicine, Chungnam National University School of Medicine, Daejeon, South Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Seoul National University Cancer Research Institute, Seoul, South Korea.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.affiliation: Korea Advanced Institute of Science and Technology, Graduate School of Medical Science and Engineering, Daejeon, South Korea.
authors.forename: J
authors.initials: J
authors.lastname: Youk
authors.affiliation: Korea Advanced Institute of Science and Technology, Graduate School of Medical Science and Engineering, Daejeon, South Korea.
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, Chungnam National University School of Medicine, Daejeon, South Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Koo
authors.affiliation: Department of Internal Medicine Seoul National University Hospital, Seoul, South Korea.
authors.forename: B
authors.initials: B
authors.lastname: Keam
authors.affiliation: Pathology, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Y K
authors.initials: YK
authors.lastname: Jeon
authors.affiliation: Seoul National University Cancer Research Institute, Seoul, South Korea.
authors.forename: J-L
authors.initials: JL
authors.lastname: Ku
authors.affiliation: Molecular Cytogenetics Core Facility, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
authors.forename: F
authors.initials: F
authors.lastname: Yang
authors.affiliation: Seoul National University Cancer Research Institute, Seoul, South Korea.|Department of Internal Medicine Seoul National University Hospital, Seoul, South Korea.
authors.forename: T M
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Korea Advanced Institute of Science and Technology, Graduate School of Medical Science and Engineering, Daejeon, South Korea.|Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Ju
mesh_terms: D000328:Adult; D002277:Carcinoma / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics; D014157:Transcription Factors; D059467:Transcriptome; D000092468:Bromodomain Containing Proteins
chemical_list: D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C109106:BRD3 protein, human; D000092468:Bromodomain Containing Proteins; C471990:BRD4-NUT fusion oncogene protein, human
keywords: NUT midline carcinoma; bromodomain and extra terminal; chromoplexy; complex genomic rearrangement; mutational signature