TY - JOUR

T1 - Redefining germline predisposition in children with molecularly characterized ependymoma

T2 - a population-based 20-year cohort

AU - Foss-Skiftesvik, Jon

AU - Stoltze, Ulrik Kristoffer

AU - van Overeem Hansen, Thomas

AU - Ahlborn, Lise Barlebo

AU - Sørensen, Erik

AU - Ostrowski, Sisse Rye

AU - Kullegaard, Solvej Margrete Aldringer

AU - Laspiur, Adrian Otamendi

AU - Melchior, Linea Cecilie

AU - Scheie, David

AU - Kristensen, Bjarne Winther

AU - Skjøth-Rasmussen, Jane

AU - Schmiegelow, Kjeld

AU - Wadt, Karin

AU - Mathiasen, René

N1 - Publisher Copyright: © 2022, The Author(s).

PY - 2022

Y1 - 2022

N2 - Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene.

AB - Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene.

KW - DNA methylation profiling

KW - Genetic susceptibility

KW - Genomics

KW - Molecular classification

KW - Pediatrics

U2 - 10.1186/s40478-022-01429-1

DO - 10.1186/s40478-022-01429-1

M3 - Journal article

C2 - 36008825

AN - SCOPUS:85137038508

VL - 10

JO - Acta neuropathologica communications

JF - Acta neuropathologica communications

SN - 2051-5960

M1 - 123

ER -