Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma.

Abstract

Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case-control data from three studies: a population-based pediatric and adolescent ependymoma case-control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case-control study from Toronto's Hospital for Sick Children and the Children's Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case-control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case-control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12-19 (P = 4.0 × 10-3), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (ORPRS = 1.67; 95% CI 1.18-2.37; P = 3.97 × 10-3) and adult-onset ependymoma (PMR-Egger = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94-1.34; P = 0.21), nor with EPN-PF-A (PMR-Egger = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.

• Authors: Chenan Zhang, Quinn T Ostrom, Eleanor C Semmes, Vijay Ramaswamy, Helen M Hansen, Libby Morimoto, Adam J de Smith, Melike Pekmezci, Zalman Vaksman, Hakon Hakonarson, Sharon J Diskin, Catherine Metayer, Glioma International Case-Control Study (GICC), Michael D Taylor, Joseph L Wiemels, Melissa L Bondy, Kyle M Walsh
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 8 Issue 1 Pg. 173 (10 28 2020) ISSN: 2051-5960 [Electronic] England
• PMID: 33115534 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ctc1 protein, human
• NAF1 protein, human
• Ribonucleoproteins
• Stn1 protein, human
• Telomere-Binding Proteins
• telomerase RNA
• RNA
• TERT protein, human
• Telomerase
• Acid Anhydride Hydrolases
• RTEL1 protein, human
• ACYP2 protein, human
• DNA Helicases

Topics

• Acid Anhydride Hydrolases (genetics)
• Adolescent
• Adult
• Age of Onset
• Brain Neoplasms (epidemiology, genetics)
• Case-Control Studies
• Child
• DNA Helicases (genetics)
• Ependymoma (epidemiology, genetics)
• Female
• Genetic Predisposition to Disease
• Humans
• Infratentorial Neoplasms (epidemiology, genetics)
• Male
• Mendelian Randomization Analysis
• RNA (genetics)
• Ribonucleoproteins (genetics)
• Telomerase (genetics)
• Telomere (metabolism)
• Telomere Homeostasis (genetics)
• Telomere-Binding Proteins (genetics)
• Young Adult