Anna Byrjalsen1,2, Thomas V O Hansen1,2, Ulrik K Stoltze1, Mana M Mehrjouy1,2, Nanna Moeller Barnkob3, Lisa L Hjalgrim2, René Mathiasen2, Charlotte K Lautrup4, Pernille A Gregersen5, Henrik Hasle6, Peder S Wehner7, Ruta Tuckuviene8, Peter Wad Sackett3, Adrian O Laspiur3, Maria Rossing9, Rasmus L Marvig9, Niels Tommerup10, Tina Elisabeth Olsen11, David Scheie11, Ramneek Gupta3, Anne-Marie Gerdes1, Kjeld Schmiegelow2,12, Karin Wadt1. 1. Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 2. Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 3. Department of Health Technology, Technical University of Denmark, Copenhagen, Denmark. 4. Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark. 5. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 6. Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark. 7. Department of Paediatric Hematology and Oncology, H. C. Andersen Children's Hospital, Odense University Hospital, Odense, Denmark. 8. Department of Paediatrics and Adolescent Medicine, Aalborg University Hospital, Aalborg, Denmark. 9. Center for Genomic Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 10. Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark. 11. Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 12. Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Abstract
PURPOSE: Historically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or were likely to have a CPS. METHODS: Children (0-17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries. RESULTS: 198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene. CONCLUSION: These results demonstrate the value of systematically screening pediatric cancer patients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed.
PURPOSE: Historically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or were likely to have a CPS. METHODS:Children (0-17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries. RESULTS: 198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene. CONCLUSION: These results demonstrate the value of systematically screening pediatric cancerpatients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed.
Authors: Catherine Goudie; Leora Witkowski; Noelle Cullinan; Lara Reichman; Ian Schiller; Melissa Tachdjian; Linlea Armstrong; Katherine A Blood; Josée Brossard; Ledia Brunga; Chantel Cacciotti; Kimberly Caswell; Sonia Cellot; Mary Egan Clark; Catherine Clinton; Hallie Coltin; Kathleen Felton; Conrad V Fernandez; Adam J Fleming; Noemi Fuentes-Bolanos; Paul Gibson; Ronald Grant; Rawan Hammad; Lynn W Harrison; Meredith S Irwin; Donna L Johnston; Sarah Kane; Lucie Lafay-Cousin; Irene Lara-Corrales; Valerie Larouche; Natalie Mathews; M Stephen Meyn; Orli Michaeli; Renée Perrier; Meghan Pike; Angela Punnett; Vijay Ramaswamy; Jemma Say; Gino Somers; Uri Tabori; My Linh Thibodeau; Annie-Kim Toupin; Katherine M Tucker; Kalene van Engelen; Stephanie Vairy; Nicolas Waespe; Meera Warby; Jonathan D Wasserman; James A Whitlock; Daniel Sinnett; Nada Jabado; Paul C Nathan; Adam Shlien; Junne Kamihara; Rebecca J Deyell; David S Ziegler; Kim E Nichols; Nandini Dendukuri; David Malkin; Anita Villani; William D Foulkes Journal: JAMA Oncol Date: 2021-12-01 Impact factor: 33.006
Authors: Iván A González; Douglas R Stewart; Kris Ann P Schultz; Amanda P Field; D Ashley Hill; Louis P Dehner Journal: Mod Pathol Date: 2021-10-01 Impact factor: 7.842
Authors: Janna A Hol; Roland P Kuiper; Freerk van Dijk; Esmé Waanders; Sophie E van Peer; Marco J Koudijs; Reno Bladergroen; Simon V van Reijmersdal; Lionel M Morgado; Jet Bliek; Maria Paola Lombardi; Saskia Hopman; Jarno Drost; Ronald R de Krijger; Marry M van den Heuvel-Eibrink; Marjolijn C J Jongmans Journal: J Clin Oncol Date: 2022-03-01 Impact factor: 50.717