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High Yield of Pathogenic Germline Mutations Causative Or Likely Causative of the Cancer Phenotype in Selected Children with Cancer Illja J

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High Yield of Pathogenic Germline Mutations Causative Or Likely Causative of the Cancer Phenotype in Selected Children with Cancer Illja J Published OnlineFirst January 19, 2018; DOI: 10.1158/1078-0432.CCR-17-1725 Personalized Medicine and Imaging Clinical Cancer Research High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer Illja J. Diets1,2, Esme Waanders1,2,3, Marjolijn J. Ligtenberg1,2,4, Diede A.G. van Bladel1,2, Eveline J. Kamping1,2, Peter M. Hoogerbrugge3, Saskia Hopman5, Maran J. Olderode-Berends6, Erica H. Gerkes6, David A. Koolen1, Carlo Marcelis1, Gijs W. Santen7, Martine J. van Belzen7, Dylan Mordaunt8, Lesley McGregor8, Elizabeth Thompson8, Antonis Kattamis9, Agata Pastorczak10, Wojciech Mlynarski10, Denisa Ilencikova11, Anneke Vulto- van Silfhout1, Thatjana Gardeitchik1, Eveline S. de Bont12, Jan Loeffen13, Anja Wagner14, Arjen R. Mensenkamp1, Roland P. Kuiper1,2,3, Nicoline Hoogerbrugge1,2, and Marjolijn C. Jongmans1,2,3,5 Abstract Purpose: In many children with cancer and characteristics Results: Four patients carried causative mutations in a known suggestive of a genetic predisposition syndrome, the genetic cause cancer-predisposing gene: TP53 and DICER1 (n ¼ 3). In another 4 is still unknown. We studied the yield of pathogenic mutations by patients, exome sequencing revealed mutations causing syn- applying whole-exome sequencing on a selected cohort of chil- dromes that might have contributed to the malignancy (EP300- dren with cancer. based Rubinstein–Taybi syndrome, ARID1A-based Coffin–Siris Experimental Design: To identify mutations in known and syndrome, ACTB-based Baraitser–Winter syndrome, and EZH2- novel cancer-predisposing genes, we performed trio-based based Weaver syndrome). In addition, we identified two genes, whole-exome sequencing on germline DNA of 40 selected KDM3B and TYK2, which are possibly involved in genetic cancer children and their parents. These children were diagnosed with predisposition. cancer and had at least one of the following features: (1) Conclusions: In our selected cohort of patients, pathogenic intellectual disability and/or congenital anomalies, (2) multi- germline mutations causative or likely causative of the cancer ple malignancies, (3) family history of cancer, or (4) an adult phenotype were found in 8 patients, and two possible novel type of cancer. We first analyzed the sequence data for germline cancer-predisposing genes were identified. Therewith, our study mutations in 146 known cancer-predisposing genes. If no shows the added value of sequencing beyond a cancer gene panel causative mutation was found, the analysis was extended to in selected patients, to recognize childhood cancer predisposition. the whole exome. Clin Cancer Res; 1–10. Ó2018 AACR. Introduction approximately 10%. This number is based on a cancer registry Asignificant fraction of pediatric cancer is caused by a and literature review already performed in 1991 (1). germline cancer-predisposing mutation, but the exact number Recognition of cancer susceptibility in children with cancer is of is unknown. In literature on this topic, the relative contribution high clinical significance. Knowledge of a cancer-predisposing of genetic predisposition to pediatric cancer is considered to be mutation may lead to modifications in treatment protocols and 1Department of Human Genetics, Radboud University Medical Center, Nijmegen, Hematology, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, the Netherlands. 2Radboud Institute for Molecular Life Sciences, Nijmegen, the the Netherlands. 14Department of Clinical Genetics, Erasmus Medical Centre, Netherlands. 3Princess Maxima Center for Pediatric Oncology, Utrecht, the Rotterdam, the Netherlands. Netherlands. 4Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands. 5Department of Genetics, University Medical Center Note: Supplementary data for this article are available at Clinical Cancer Utrecht, Utrecht, the Netherlands. 6Department of Genetics, University of Research Online (http://clincancerres.aacrjournals.org/). Groningen, University Medical Center Groningen, Groningen, the Netherlands. 7 Department of Clinical Genetics, Leiden University Medical Center, Leiden, the R.P. Kuiper, N. Hoogerbrugge, and M.C. Jongmans contributed equally to this 8 Netherlands. Department of Genetics and Molecular Pathology, SA Pathology, article. Women's and Children's Hospital, North Adelaide, Australia. 9First Department of Pediatrics, Athens University Medical School, Athens, Greece. 10Department Corresponding Author: Marjolijn C. Jongmans, Radboud University Medical of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands. Phone: Lodz, Lodz, Poland. 112nd Pediatric Department, Children's University Hospital, 003124-3610868; E-mail: [email protected]. Comenius University, Bratislava, Slovakia. 12Department of Pediatric Oncology doi: 10.1158/1078-0432.CCR-17-1725 and Hematology, Beatrix Children's Hospital, University Medical Center Gronin- gen, Groningen, the Netherlands. 13Department of Pediatric Oncology and Ó2018 American Association for Cancer Research. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst January 19, 2018; DOI: 10.1158/1078-0432.CCR-17-1725 Diets et al. Most centers for pediatric oncology currently may not be able to Translational Relevance analyze all children with cancer using NGS techniques to search Knowledge of a cancer-predisposing mutation in a child can for germline-predisposing mutations. Selecting the right patients be beneficial in terms of treatment choices, surveillance pro- for germline testing will then be important. Therefore, we studied tocols, and genetic counseling of the family. This study sought the yield of germline WES if applied on a selected cohort of to determine the proportion of germline genetic mutations in childhood cancer patients with a high a priori chance of having a selected children with cancer, by applying whole-exome genetic cancer-predisposing mutation. Because we also aimed to sequencing on patient–parent trios, with subsequent cancer identify novel cancer-predisposing genes, we used both a cancer gene panel-restricted analysis as well as exome-wide analysis. gene panel analysis and whole-exome analysis. We included With this strategy, germline pathogenic mutations were iden- parental DNA to facilitate the interpretation of de novo and tified in 20% of the children, showing the value of whole- biallelic mutations. With this strategy, we found a high yield of exome sequencing in this selected cohort. pathogenic mutations in our selected childhood cancer cohort. Materials and Methods Enrollment of the patients the application of cancer surveillance for early detection of second Patients with childhood cancer who fulfilled one or more of primary malignancies. In addition, it will enable genetic counsel- the following criteria were included: (1) The presence of con- ing and cancer surveillance for family members. genital anomalies without a clear infectious or environmental Thepresenceofgermlinecancer-predisposingmutationsin cause and/or intellectual disability (ID), defined by an Intelli- children can be suspected based on specific hallmarks such as a gence Quotient score below 70, with an origin before the positive family history of cancer, the development of multiple diagnosis and treatment of cancer; (2) the presence of a second malignancies, or the presence of congenital anomalies (2–4). primary malignancy, excluding patients in whom no clear Based on these hallmarks, we have developed a practical tool distinction can be made between a second primary malignancy to improve the selection of childhood cancer patients eligible and a therapy-related secondary cancer; (3) the presence of for referral to a clinical geneticist for genetic counseling and afamilyhistoryofcancer,defined as having one or more first- genetic testing (2). However, even if hallmarks suggesting a or second-degree relative(s) with childhood cancer; (4) the cancer-predisposing mutation are present in a child, the diag- diagnosis of an adult type of cancer in a child, defined as a nosis of a specific syndrome relies on the physicians to recog- malignancy frequent in the adult population, but with an nize this syndrome and to ask for the right targeted genetic test. incidence of less than 1 in a million children (age 0–18) per In daily practice, underlying syndromes are often missed due to year (Table 1). Patients who fulfilled our inclusion criteria were their heterogeneity and the lack of a recognizable clinical referred by pediatric oncologists and geneticists from different phenotype (3, 5). centers in the Netherlands (n ¼ 32) and from abroad (n ¼ 8). In recent years, next-generation sequencing (NGS) techniques Prior to inclusion, most patients had undergone an extensive have become available and are gradually being implemented in diagnostic workup for germline genetic aberrations, including routine clinical care (6). For many syndromes, the application of 250K SNP array analysis, which did not lead to a diagnosis. these techniques has revealed that the phenotypic spectrum is When the clinician thought of a specific (cancer predisposing) much broader than the clinical diagnostic criteria set by physi- syndrome, targeted gene tests were performed before inclusion cians (7). In addition, NGS techniques have proven their value in in the study. Details about these tests
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