Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants

Jennifer L. Stundon, Heba Ijaz, Krutika S. Gaonkar, Rebecca S. Kaufman, Run Jin, Anastasios Karras, Zalman Vaksman, Jung Kim, Ryan J. Corbett, Matthew R. Lueder, Daniel P. Miller, Yiran Guo, Mariarita Santi, Marilyn Li, Gonzalo Lopez, Phillip B. Storm, Adam C. Resnick, Angela J. Waanders, Suzanne P. MacFarland, Douglas R. StewartSharon J. Diskin, Jo Lynne Rokita*, Kristina A. Cole

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Background: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. Methods: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. Results: ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT- pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. Conclusions: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.

Original languageEnglish (US)
Pages (from-to)1331-1342
Number of pages12
JournalNeuro-oncology
Volume25
Issue number7
DOIs
StatePublished - Jul 1 2023

Funding

This work was supported by National Institutes of Health grant U2C-CA233285 (K.A.C.), National Institutes of Health 5T32CA009615-30 (J.L.S.), National Institutes of \u2028Health 2K12HD043245-16 (J.L.S.), National Institutes of Health R03-CA23036 (S.J.D.), National Institutes of Health Contract No. HHSN261200800001E (S.J.D.), an Alex\u2019s Lemonade Stand Foundation Young Investigator Award (J.L.R.), the Matthew Larson Foundation (K.A.C.), the Marlene Shlomchik Fellowship for Cancer Research (J.L.S.), the Division of Neurosurgery at the Children\u2019s Hospital of Philadelphia (P.J.S., A.C.R.), and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute.

Keywords

  • ATRX
  • Telomere
  • alternative lengthening of telomeres
  • mismatch repair
  • pHGG
  • pediatric brain tumors

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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