Genetic predisposition & evolutionary traces of pediatric cancer risk

Genetic predisposition & evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Genetic predisposition & evolutionary traces of pediatric cancer risk : a prospective 5-year population-based genome sequencing study of children with CNS tumors. / Stoltze, Ulrik Kristoffer; Foss-Skiftesvik, Jon; van Overeem Hansen, Thomas; Byrjalsen, Anna; Sehested, Astrid; Scheie, David; Mikkelsen, Torben Stamm; Rasmussen, Simon; Bak, Mads; Okkels, Henrik; Callesen, Michael Thude; Skjøth-Rasmussen, Jane; Gerdes, Anne-Marie; Schmiegelow, Kjeld; Mathiasen, René; Wadt, Karin.

In: Neuro-Oncology, Vol. 25, No. 4, 2023, p. 761-773.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Stoltze, UK, Foss-Skiftesvik, J, van Overeem Hansen, T, Byrjalsen, A, Sehested, A, Scheie, D, Mikkelsen, TS, Rasmussen, S, Bak, M, Okkels, H, Callesen, MT, Skjøth-Rasmussen, J, Gerdes, A-M, Schmiegelow, K, Mathiasen, R & Wadt, K 2023, 'Genetic predisposition & evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors', Neuro-Oncology, vol. 25, no. 4, pp. 761-773. https://doi.org/10.1093/neuonc/noac187

APA

Stoltze, U. K., Foss-Skiftesvik, J., van Overeem Hansen, T., Byrjalsen, A., Sehested, A., Scheie, D., Mikkelsen, T. S., Rasmussen, S., Bak, M., Okkels, H., Callesen, M. T., Skjøth-Rasmussen, J., Gerdes, A-M., Schmiegelow, K., Mathiasen, R., & Wadt, K. (2023). Genetic predisposition & evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors. Neuro-Oncology, 25(4), 761-773. https://doi.org/10.1093/neuonc/noac187

Vancouver

Stoltze UK, Foss-Skiftesvik J, van Overeem Hansen T, Byrjalsen A, Sehested A, Scheie D et al. Genetic predisposition & evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors. Neuro-Oncology. 2023;25(4):761-773. https://doi.org/10.1093/neuonc/noac187

Author

Stoltze, Ulrik Kristoffer ; Foss-Skiftesvik, Jon ; van Overeem Hansen, Thomas ; Byrjalsen, Anna ; Sehested, Astrid ; Scheie, David ; Mikkelsen, Torben Stamm ; Rasmussen, Simon ; Bak, Mads ; Okkels, Henrik ; Callesen, Michael Thude ; Skjøth-Rasmussen, Jane ; Gerdes, Anne-Marie ; Schmiegelow, Kjeld ; Mathiasen, René ; Wadt, Karin. / Genetic predisposition & evolutionary traces of pediatric cancer risk : a prospective 5-year population-based genome sequencing study of children with CNS tumors. In: Neuro-Oncology. 2023 ; Vol. 25, No. 4. pp. 761-773.

Bibtex

@article{08475c4c673a4fbfadd110cdf35bb5e8,

title = "Genetic predisposition & evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors",

abstract = "BACKGROUND: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking.METHODS: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3,543 close relatives.RESULTS: Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (p=0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (p=5e-4) and all other genes (p=5e-17). Based on this observation, we expanded our analysis to 2 986 genes exhibiting high evolutionary constraint in 141 456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity - raising the question of the role of other highly constrained gene alterations detected.CONCLUSIONS: ∽10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.",

author = "Stoltze, {Ulrik Kristoffer} and Jon Foss-Skiftesvik and {van Overeem Hansen}, Thomas and Anna Byrjalsen and Astrid Sehested and David Scheie and Mikkelsen, {Torben Stamm} and Simon Rasmussen and Mads Bak and Henrik Okkels and Callesen, {Michael Thude} and Jane Skj{\o}th-Rasmussen and Anne-Marie Gerdes and Kjeld Schmiegelow and Ren{\'e} Mathiasen and Karin Wadt",

note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",

year = "2023",

doi = "10.1093/neuonc/noac187",

language = "English",

volume = "25",

pages = "761--773",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "4",

}

RIS

TY - JOUR

T1 - Genetic predisposition & evolutionary traces of pediatric cancer risk

T2 - a prospective 5-year population-based genome sequencing study of children with CNS tumors

AU - Stoltze, Ulrik Kristoffer

AU - Foss-Skiftesvik, Jon

AU - van Overeem Hansen, Thomas

AU - Byrjalsen, Anna

AU - Sehested, Astrid

AU - Scheie, David

AU - Mikkelsen, Torben Stamm

AU - Rasmussen, Simon

AU - Bak, Mads

AU - Okkels, Henrik

AU - Callesen, Michael Thude

AU - Skjøth-Rasmussen, Jane

AU - Gerdes, Anne-Marie

AU - Schmiegelow, Kjeld

AU - Mathiasen, René

AU - Wadt, Karin

PY - 2023

Y1 - 2023

N2 - BACKGROUND: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking.METHODS: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3,543 close relatives.RESULTS: Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (p=0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (p=5e-4) and all other genes (p=5e-17). Based on this observation, we expanded our analysis to 2 986 genes exhibiting high evolutionary constraint in 141 456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity - raising the question of the role of other highly constrained gene alterations detected.CONCLUSIONS: ∽10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.

AB - BACKGROUND: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking.METHODS: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3,543 close relatives.RESULTS: Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (p=0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (p=5e-4) and all other genes (p=5e-17). Based on this observation, we expanded our analysis to 2 986 genes exhibiting high evolutionary constraint in 141 456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity - raising the question of the role of other highly constrained gene alterations detected.CONCLUSIONS: ∽10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.

U2 - 10.1093/neuonc/noac187

DO - 10.1093/neuonc/noac187

M3 - Journal article

C2 - 35902210

VL - 25

SP - 761

EP - 773

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 4

ER -

ID: 319121015