PREreviews of Chromosome-arm-specific telomere length governs dual modes of structural genome evolution in IDH-mutant astrocytoma

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Chromosome-arm-specific telomere length governs dual modes of structural genome evolution in IDH-mutant astrocytoma

by Maryam Jehangir, Kristen L. Drucker, Ayse Keskus, T. Rhyker Ranallo-Benavidez, Orlena Benamozig, Thomas Kollmeyer, Terry C. Burns, Caterina Giannini, Benjamin R. Kipp, Stephen J. Murphy, Amber R. Bridgeman, Jesse R. Walsh, Ramanath Majumdar, Daniel Lachance, Jeanette Eckel-Passow, Ofer Shoshani, Mikhail Kolmogorov, Robert B. Jenkins, and Floris P. Barthel

Posted: April 23, 2026
Server: bioRxiv
DOI: 10.64898/2026.04.22.720226

Abstract

IDH-mutant astrocytomas maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, producing extreme inter-arm telomere length heterogeneity, yet how this heterogeneity shapes structural genome evolution remains unknown. Using Oxford Nanopore long-read sequencing of 20 IDH-mutant astrocytomas, we profiled structural variants (SVs), copy number variants, extrachromosomal DNA (ecDNA) and measured allele-specific telomere lengths from individual long reads. We identified pervasive complex rearrangements, including chromothripsis and foldback events consistent with breakage-fusion-bridge cycles, and widespread ecDNAs. SV breakpoints were enriched at telomeric and centromeric regions regardless of local telomere length, revealing constitutive structural fragility. Arm-level telomere length analysis uncovered a dual-mode model: arms with short telomeres preferentially harbored breakage-associated events, while arms with long ALT-maintained telomeres were enriched for ecDNA and amplification-associated events. These findings identify chromosome-arm-specific telomere length as a determinant of structural genome evolution in ALT-driven tumors.

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PREreview by Joseph Biggane et al. of ASAPbio Cell Biology Crowd

Authored by Joseph Biggane, Timothy En Haw Chan, Joseph Biggane, Debraj Manna, Haofu Huang, Nitya Khetarpal, Briana E. Pinales, Chinyere Mary-Cynthia Ikele, Sarah E. Gilmour, Diptarup Mallick, and 1 other author of ASAPbio Cell Biology Crowd

This review reflects comments and contributions by Joseph Biggane, Nitya Khetarpal, Yuka Gliday, Sarah Gilmour, Diptarup Mallick, Chinyere Mary-Cynthia Ikele, Timothy En Haw Chan, Haofu Huang, Briana Pinales, and Debraj Manna. Review synthesized by Joseph Biggane.

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