Genome-wide association study across pediatric central nervous system tumors implicates shared predisposition and points
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ORIGINAL ARTICLE
Genome-wide association study across pediatric central nervous system tumors implicates shared predisposition and points to 1q25.2 (PAPPA2) and 11p12 (LRRC4C) as novel candidate susceptibility loci Jon Foss-Skiftesvik 1,2,3 & Christian Munch Hagen 2,4,5 & René Mathiasen 3 & Dea Adamsen 2,5 & Marie Bækvad-Hansen 2,5 & Anders D. Børglum 5,6,7 & Merete Nordentoft 4,5,8 & Thomas Werge 4,5,9 & Michael Christiansen 2,5 & Kjeld Schmiegelow 3,4 & Marianne Juhler 1,4,10 & Preben Bo Mortensen 5,11,12 & David Michael Hougaard 2,5 & Jonas Bybjerg-Grauholm 2,5 Received: 13 August 2020 / Accepted: 26 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Introduction Central nervous system (CNS) tumors constitute the most common form of solid neoplasms in children, but knowledge on genetic predisposition is sparse. In particular, whether susceptibility attributable to common variants is shared across CNS tumor types in children has not been investigated. The purpose of this study was to explore potential common genetic risk variants exhibiting pleiotropic effects across pediatric CNS tumors. We also investigated whether such susceptibility differs between early and late onset of disease. Method A Danish nationwide genome-wide association study (GWAS) of 1,097 consecutive patients (< 15 years of age) with CNS tumors and a cohort of 4,745 population-based controls. Results For both the overall cohort and patients diagnosed after the age of four, the strongest association was rs12064625 which maps to PAPPA2 at 1q25.2 (p = 3.400 × 10−7 and 9.668 × 10−8, respectively). PAPPA2 regulates local bioavailability of insulinlike growth factor I (IGF-I). IGF-I is fundamental to CNS development and is involved in tumorigenesis across a wide range of different cancers. For the younger children, the strongest association was provided by rs11036373 mapping to LRRC4C at 11p12 (p = 7.620 × 10−7), which encoded protein acts as an axon guidance molecule during CNS development and has not formerly been associated with brain tumors. Discussion This GWAS indicates shared susceptibility attributable to common variants across pediatric CNS tumor types. Variations in genetic loci with roles in CNS development appear to be involved, possibly via altered IGF-I related pathways. Keywords GWAS . Childhood . Brain tumor . Germline . Single nucleotide polymorphism . Common variants
* Jon Foss-Skiftesvik [email protected] 1
Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark
2
Danish Center for Neonatal Screening, Department of Congenital Diseases, Statens Serum Institut, Copenhagen, Denmark
3
Department of Pediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark
4
Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
5
The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark
6
Departme
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