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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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. / Foss-Skiftesvik, Jon; Hagen, Christian Munch; Mathiasen, René; Adamsen, Dea; Bækvad-Hansen, Marie; Børglum, Anders D.; Nordentoft, Merete; Werge, Thomas; Christiansen, Michael; Schmiegelow, Kjeld; Juhler, Marianne; Mortensen, Preben Bo; Hougaard, David Michael; Bybjerg-Grauholm, Jonas.
In: Child's Nervous System, Vol. 37, 2021, p. 819–830.Research output: Contribution to journal › Journal article › Research › peer-review
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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
Y1 - 2021
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 - Brain tumor
KW - Childhood
KW - Common variants
KW - Germline
KW - GWAS
KW - Single nucleotide polymorphism
U2 - 10.1007/s00381-020-04946-3
DO - 10.1007/s00381-020-04946-3
M3 - Journal article
C2 - 33226468
AN - SCOPUS:85096434312
VL - 37
SP - 819
EP - 830
JO - Child's Nervous System
JF - Child's Nervous System
SN - 0256-7040
ER -
ID: 253140645