Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX
Alexandre de Nonneville, Roger R. Reddel
Abstract
he PCAWG Consortium has recently released an integrative re-analysis of a large set of tumor whole genome sequence (WGS) data from 2658 cancer patients across 38 different primary tumor sites 1 . In a companion paper, Sieverling et al. built a random forest classifier for the telomere maintenance mechanism (TMM) by regarding truncating ATRX or DAXX alterations, referred to as ATRX/DAXX trunc , vs. TERT modifications (TERT mod ; i.e., promoter mutations amplifications structural variations), as indicators of alternative lengthening of telomeres (ALT) vs. telomerase 2 . We show here that equating ATRX/ DAXX trunc and TERT mod with ALT and telomerase, respectively, results in TMM predictions which do not correlate well with TMM assay data. Although ATRX/DAXX trunc mutations are associated with TMM, most tumors do not harbor them and they are heterogeneously distributed in ALT-positive (ALT + ) tumors of different types, as are TERT mod in telomerase-positive tumors