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ALT in Pediatric High-Grade Gliomas Can Occur without ATRX Mutation and is Enriched in Patients with Pathogenic Germline MMR Variants
Jennifer L Stundon, Heba Ijaz 1 2, Krutika S Gaonkar 3 4 5, Rebecca S Kaufman 6 4, Run Jin 3 5, Anastasios Karras 6, Zalman Vaksman 6 4, Jung Kim 7, Ryan J Corbett 3 5, Matthew R Lueder 3 5, Daniel P Miller 3 5, Yiran Guo 3 5, Mariarita Santi 8, Marilyn Li 8, Gonzalo Lopez 6, Phillip B Storm 3 5, Adam C Resnick 3 5, Angela J Waanders 9 10, Suzanne P MacFarland 6 1, Douglas R Stewart 7, Sharon J Diskin 6 1 4 11, Jo Lynne Rokita 3 4 5, Kristina A Cole 6 1 11
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 glioma (pHGG) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.
Results: ALT is common in pHGG (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGG and in 30% of ALT- pHGG. 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+ pHGG, 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 development of ALT in patients with pHGG.
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 glioma (pHGG) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.
Results: ALT is common in pHGG (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGG and in 30% of ALT- pHGG. 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+ pHGG, 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 development of ALT in patients with pHGG.
PMID: 36541551
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