title: Whole Exome- and mRNA-Sequencing of an AT/RT Case Reveals Few Somatic Mutations and Several Deregulated Signalling Pathways in the Context of SMARCB1 Deficiency.
abstract: BACKGROUND
  AT/RTs are rare aggressive brain tumours, mainly affecting young children. Most cases present with genetic inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodeling complex. We have performed whole exome- and mRNA-sequencing on an early onset AT/RT case for detection of genetic events potentially contributing to the disease.
  
  
  RESULTS
  A de novo germline variant in SMARCB1, c.601C>T p.Arg201∗, in combination with somatic deletion of the healthy allele is likely the major tumour causing event. Only seven somatic small scale mutations were discovered (hitting SEPT03, H2BFM, ZIC4, HIST2H2AB, ZIK1, KRTAP6-3, and IFNA8). All were found with subclonal allele frequencies (range 5.7-17%) and none were expressed. However, besides SMARCB1, candidate genes affected by predicted damaging germline variants that were expressed were detected (KDM5C, NUMA1, and PCM1). Analysis of differently expressed genes revealed many dysregulated pathways in the tumour, such as cell cycle, CXCR4 pathway, GPCR-signalling, and neuronal system. FGFR1, CXCR4, and MDK were upregulated and may represent possible drug targets.
  
  
  CONCLUSIONS
  The loss of SMARCB1 function leads to AT/RT development and deregulated genes and pathways. Additional predisposing events may however contribute. Studies utilizing NGS technologies in larger cohorts will probably identify recurrent genetic and epigenetic alterations and molecular subgroups with implications for clinical practice and development of targeted therapies.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Sandgren
authors.affiliation: Department of Women and Child Health, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Holm
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Marino
authors.affiliation: Clinical Pathology/Cytology, Karolinska University Hospital at Solna, 171 76 Stockholm, Sweden.
authors.forename: Jurate
authors.initials: J
authors.lastname: Asmundsson
authors.affiliation: Department of Women and Child Health, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Grillner
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Monica
authors.initials: M
authors.lastname: Nistér
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Teresita
authors.initials: T
authors.lastname: Díaz de Ståhl
mesh_terms: D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D016678:Genome / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D000067552:Mutation Accumulation; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000235:genetics*; D000071796:SMARCB1 Protein; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013724:Teratoma / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors