High yield of pathogenic germline mutations causative or likely causative of the cancer phenotype in selected children with cancer

Illja J. Diets, Esmé Waanders, Marjolijn J. Ligtenberg, Diede A.G. van Bladel, Eveline J. Kamping, Peter M. Hoogerbrugge, Saskia Hopman, Maran J. Olderode-Berends, Erica H. Gerkes, David A. Koolen, Carlo Marcelis, Gijs W. Santen, Martine J. van Belzen, Dylan Mordaunt, Lesley McGregor, Elizabeth Thompson, Antonis Kattamis, Agata Pastorczak, Wojciech Mlynarski, Denisa IlencikovaAnneke Vulto-Van Silfhout, Thatjana Gardeitchik, Eveline S. de Bont, Jan Loeffen, Anja Wagner, Arjen R. Mensenkamp, Roland P. Kuiper, Nicoline Hoogerbrugge, Marjolijn C. Jongmans

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)


Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer.

Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to

Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n ¼ 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein–Taybi syndrome, ARID1A-based Coffin–Siris syndrome, ACTB-based Baraitser–Winter syndrome, and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition.

Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition.

Original languageEnglish
Pages (from-to)1594-1603
Number of pages10
JournalClinical Cancer Research
Issue number7
Publication statusPublished - 1 Apr 2018
Externally publishedYes

Bibliographical note

Funding Information:
This study was funded by the KiKa Foundation (project 127). E. Waanders is a fellow from the Dutch Cancer Society (KUN2012-5366). The funding agencies did not have influence on generating and publishing the data.

Publisher Copyright:
© 2018 American Association for Cancer Research.


  • children
  • cancer
  • genetic
  • mutations
  • cancer-predisposing gene
  • causative
  • germline
  • pathogenic
  • predisposing genes
  • intellectual disability
  • congenital anomalies
  • malignancies
  • family history


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