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.

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Persistent URL dx.doi.org/10.1158/1078-0432.CCR-17-1725, hdl.handle.net/1765/113205
Journal Clinical Cancer Research
Diets, I.J. (Illja J.), Waanders, E. (Esme), Ligtenberg, M.J, van Bladel, D.A.G. (Diede A.G.), Kamping, E, Hoogerbrugge, P.M, … Jongmans, M.C.J. (2018). High yield of pathogenic germline mutations causative or likely causative of the cancer phenotype in selected children with cancer. Clinical Cancer Research, 24(7), 1594–1603. doi:10.1158/1078-0432.CCR-17-1725