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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.  Conclusion . 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.

biomed research international

Whole Exome- and mRNA-Sequencing of an AT/RT Case Reveals Few Somatic Mutations and Several Deregulated Signalling Pathways in the Context of<i>SMARCB1</i>Deficiency

Whole Exome- and mRNA-Sequencing of an AT/RT Case Reveals Few Somatic Mutations and Several Deregulated Signalling Pathways in the Context ofSMARCB1Deficiency