folder

Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

Authors

  • S.A. Hartlieb
  • L. Sieverling
  • M. Nadler-Holly
  • M. Ziehm
  • U.H. Toprak
  • C. Herrmann
  • N. Ishaque
  • K. Okonechnikov
  • M. Gartlgruber
  • Y.G. Park
  • E.M. Wecht
  • L. Savelyeva
  • K.O. Henrich
  • C. Rosswog
  • M. Fischer
  • B. Hero
  • D.T.W. Jones
  • E. Pfaff
  • O. Witt
  • S.M. Pfister
  • Ri. Volckmann
  • J. Koster
  • K. Kiesel
  • K. Rippe
  • S. Taschner-Mandl
  • P. Ambros
  • B. Brors
  • M. Selbach
  • L. Feuerbach
  • F. Westermann

Journal

  • Nature Communications

Citation

  • Nat Commun 12 (1): 1269

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.


DOI

doi:10.1038/s41467-021-21247-8