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

36 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 the whole exome.Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n = 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. Clin Cancer Res; 24(7); 1594-603. ©2018 AACR.

Original languageEnglish
Pages (from-to)1594-1603
Number of pages10
JournalClin Cancer Res
Issue number7
Publication statusPublished - 1 Apr 2018


  • Abnormalities, Multiple/genetics
  • Adolescent
  • Child
  • Child, Preschool
  • Congenital Hypothyroidism/genetics
  • Craniofacial Abnormalities/genetics
  • Exome/genetics
  • Face/abnormalities
  • Female
  • Genetic Predisposition to Disease/genetics
  • Genotype
  • Germ-Line Mutation/genetics
  • Hand Deformities, Congenital/genetics
  • Humans
  • Infant
  • Intellectual Disability/genetics
  • Male
  • Micrognathism/genetics
  • Neck/abnormalities
  • Neoplasms/genetics
  • Phenotype
  • Rubinstein-Taybi Syndrome/genetics
  • Whole Exome Sequencing/methods


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