High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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.<b>Results:</b> Four patients carried causative mutations in a known cancer-predisposing gene: <i>TP53</i> and <i>DICER1</i> (<i>n</i> = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (<i>EP300</i>-based Rubinstein-Taybi syndrome, <i>ARID1A</i>-based Coffin-Siris syndrome, <i>ACTB</i>-based Baraitser-Winter syndrome, and <i>EZH2</i>-based Weaver syndrome). In addition, we identified two genes, <i>KDM3B</i> and <i>TYK2</i>, which are possibly involved in genetic cancer predisposition.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 24(7); 1594-603. ©2018 AACR</i>.