High Yield of Causative Mutations by Whole Exome Sequencing in Selected Individuals with Childhood Cancer

I. Diets, E. Waanders, A. Mensenkamp, M. Ligtenberg, E. Kamping, P. Hoogerbrugge, M. Olderode-Berends, D. Koolen, G. Santen, D. Mordaunt, A. Kattamis, A. Pastorczak, A. Vulto-van Silfhout, E. de Bont, J. Loeffen, R. Kuiper, N. Hoogerbrugge, M. Jongmans

Research output: Contribution to journalMeeting Abstractpeer-review


Background/Objectives: Childhood cancer predisposition shows extensive genetic heterogeneity with currently over 100 predisposing conditions described and likely many to be identified. Recognition of genetic predisposition in a child with cancer may lead to better treatment choices and surveillance options.
Design/Methods: We applied whole exome sequencing on germline DNA of children and their parents. These children were diagnosed with cancer and had at least one of the following features: intellectual disability (ID) or congenital anomalies, adult type of cancer, a family history for childhood cancer or multiple primary malignancies. All included cases remained undiagnosed after consultation by a clinical geneticist and often multiple genetic tests. Results: Analysis of the 45 included patients resulted in a high yield of causative mutations. Five patients carried mutations in the known cancer genes TP53, DICER1 (n=3) and ETV6. In five children, exome sequencing revealed syndromes that likely contributed to their malignancy(EP300 based Rubinstein Taybi syndrome in a girl with AML; EZH2 based Weaver syndrome in a boy with Burkitt lymphoma, PHF6 based Borjeson-Forssman-Lehmann syndrome in a boy with a low grade glioma and in two boys with ALL ARID1A based Coffin Siris syndrome and ACTB based Baraitser Winter syndrome). In addition, we identified several novel candidate genes for childhood cancer. For instance, in a girl with lymphoma and congenital anomalies of the kidney (CAKUT) and uterus a de novo mutation in E4F1 (p.Arg90*) was found, which could explain both conditions. E4F1 is a binding partner of HNF1𝛽, a gene known to be involved in CAKUT. In addition, E4F1 is a key posttranslational regulator of TP53.Conclusion: Our study shows the value of exome sequencing in the field of childhood cancer predisposition, both to facilitate the diagnosis of known syndromes as well as to trace novel genes involved in cancer susceptibility.
Original languageEnglish
Pages (from-to)S13-S14
Number of pages2
JournalPediatric Blood and Cancer
Issue numberS3
Publication statusPublished - Nov 2016
Externally publishedYes


  • Childhood
  • Cancer
  • treatment
  • genetic
  • heterogeneity
  • germline
  • DNA
  • intellectual disability


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