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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

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@article{dddb57f4a93c4d2abbc039635cdaee02,
title = "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",
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 insulin-like 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",
author = "Jon Foss-Skiftesvik and Hagen, {Christian Munch} and Ren{\'e} Mathiasen and Dea Adamsen and Marie B{\ae}kvad-Hansen and B{\o}rglum, {Anders D} and Merete Nordentoft and Thomas Werge and Michael Christiansen and Kjeld Schmiegelow and Marianne Juhler and Mortensen, {Preben Bo} and Hougaard, {David Michael} and Jonas Bybjerg-Grauholm",
year = "2021",
month = mar,
doi = "10.1007/s00381-020-04946-3",
language = "English",
volume = "37",
pages = "819--830",
journal = "Child's Nervous System",
issn = "0256-7040",
publisher = "Springer",
number = "3",

}

RIS

TY - JOUR

T1 - 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

AU - Foss-Skiftesvik, Jon

AU - Hagen, Christian Munch

AU - Mathiasen, René

AU - Adamsen, Dea

AU - Bækvad-Hansen, Marie

AU - Børglum, Anders D

AU - Nordentoft, Merete

AU - Werge, Thomas

AU - Christiansen, Michael

AU - Schmiegelow, Kjeld

AU - Juhler, Marianne

AU - Mortensen, Preben Bo

AU - Hougaard, David Michael

AU - Bybjerg-Grauholm, Jonas

PY - 2021/3

Y1 - 2021/3

N2 - 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 insulin-like 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.

AB - 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 insulin-like 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.

KW - GWAS

KW - Childhood

KW - Brain tumor

KW - Germline

KW - Single nucleotide polymorphism

KW - Common variants

U2 - 10.1007/s00381-020-04946-3

DO - 10.1007/s00381-020-04946-3

M3 - Journal article

C2 - 33226468

VL - 37

SP - 819

EP - 830

JO - Child's Nervous System

JF - Child's Nervous System

SN - 0256-7040

IS - 3

ER -

ID: 61346467