Search

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.

Supplementary Table S1 - Cancer gene panel Supplementary Table S2 - Patients with multiple malignancies Supplementary Table S3 - Tumor types of index patients Supplementary Table S4 - Candidate genes Supplementary Table S5 - Overview of clinical features and mutations found in category 1 (ID and/or congenital anomalies) Supplementary Table S6 - Overview of clinical features and mutations found in category 2 (cancer twice) Supplementary Table S7 - Overview of clinical features and mutations found in category 3 (family history) Supplementary Table S8 - Overview of clinical features and mutations found in category 4 (adult type of cancer) Supplementary Table S9 - Overview of clinical features and mutations found in category 5 (multiple reasons for inclusion) Supplementary Figure S1 - Detection of mosaic mutation in ARID1A Supplementary Figure S2 - Family tree of case #04 Supplementary Figure S3 - Family tree of case #05 Supplementary Figure S4 - Family tree of case #07 Supplementary Figure S5 - Family tree of case #10 Supplementary Figure S6 - Family tree of case #12 Supplementary Figure S7 - Family tree of case #17 Supplementary Figure S8 - Family tree of case #21 Supplementary Figure S9 - Family tree of case #22 Supplementary Figure S10 - Family tree of case #24 Supplementary Figure S11 - Family tree of case #27 Supplementary Figure S12 - Family tree of case #28 Supplementary Figure S13 - Family tree of case #29 Supplementary Figure S14 - Family tree of case #34 Supplementary Figure S15 - Family tree of case #36 Supplementary Figure S16 - Family tree of case #39

This file contains all mutations identified in all patients.