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.

Autor:	Stundon JL; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania,USA., Ijaz H; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania,USA., Gaonkar KS; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Kaufman RS; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Jin R; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Karras A; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Vaksman Z; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Kim J; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland,USA., Corbett RJ; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Lueder MR; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Miller DP; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Guo Y; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Santi M; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Li M; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Lopez G; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Storm PB; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Resnick AC; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Waanders AJ; Division of Hematology, Oncology, NeuroOncology, and Stem Cell Transplant, Ann & Robert H Lurie Children's Hospital of Chicago, Illinois,USA.; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois,USA., MacFarland SP; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania,USA., Stewart DR; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland,USA., Diskin SJ; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania,USA.; Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,USA., Rokita JL; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA., Cole KA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,USA.; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania,USA.; Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania,USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2023 Jul 06; Vol. 25 (7), pp. 1331-1342.
DOI:	10.1093/neuonc/noac278
Abstrakt:	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. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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