Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort

Abstract

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.

Keywords: DNA methylation profiling; Genetic susceptibility; Genomics; Molecular classification; Pediatrics.

Fig. 1

Graphic overview of the cohort (n = 43 children) and methods employed

Fig. 2

Sankey plot illustrating original histopathological diagnosis (left) for 43 children registered with ependymoma and corresponding tumor methylation class (right). CPS, cancer predisposition syndrome; ANA-EPN, ependymoma WHO 3; EPN, ependymoma WHO 2; MYX-EPN, myxopapillary ependymoma WHO 2; GBM, atypical glioblastoma with several differential diagnoses considered; where clinical methylation profiling resulted in alteration of the diagnosis; EBLASTOMA, ependymoblastoma incorrectly registered in the Danish Childhood Cancer Registry as ependymoma; NA, not available

Fig. 3

Overview of resulting molecular tumor classification for the four patients with detected pathogenic germline variants