Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome
Sabine Hartlieb, Lina Sieverling, Michal Nadler-Holly, Matthias Ziehm, Umut H. Toprak, Carl Herrmann, Naveed Ishaque, Konstantin Okonechnikov, Moritz Gartlgruber, Young‐Gyu Park, Elisa M. Wecht, Larissa Savelyeva, Kai‐Oliver Henrich, Carolina Rosswog, Matthias Fischer, Barbara Hero, David Jones, Elke Pfaff, Olaf Witt, Stefan M. Pfister, Richard Volckmann, Jan Köster, Katharina Kiesel, Karsten Rippe, Sabine Taschner‐Mandl, Peter F. Ambros, Benedikt Brors, Matthias Selbach, Lars Feuerbach, Frank Westermann
Abstract
Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.