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

Autor:	Diets IJ; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.; Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands., Waanders E; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.; Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Ligtenberg MJ; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.; Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.; Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands., van Bladel DAG; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.; Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands., Kamping EJ; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.; Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands., Hoogerbrugge PM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Hopman S; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Olderode-Berends MJ; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Gerkes EH; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Koolen DA; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Marcelis C; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Santen GW; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands., van Belzen MJ; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands., Mordaunt D; Department of Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, Australia., McGregor L; Department of Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, Australia., Thompson E; Department of Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, Australia., Kattamis A; First Department of Pediatrics, Athens University Medical School, Athens, Greece., Pastorczak A; Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland., Mlynarski W; Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland., Ilencikova D; 2nd Pediatric Department, Children's University Hospital, Comenius University, Bratislava, Slovakia., van Silfhout AV; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Gardeitchik T; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., de Bont ES; Department of Pediatric Oncology and Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands., Loeffen J; Department of Pediatric Oncology and Hematology, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, the Netherlands., Wagner A; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands., Mensenkamp AR; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Kuiper RP; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.; Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Hoogerbrugge N; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.; Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands., Jongmans MC; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. Marjolijn.Jongmans@radboudumc.nl.; Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2018 Apr 01; Vol. 24 (7), pp. 1594-1603. Date of Electronic Publication: 2018 Jan 19.
DOI:	10.1158/1078-0432.CCR-17-1725
Abstrakt:	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 . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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