Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX

Abstract The PCAWG Consortium has recently released an unprecedented set of tumor whole genome sequence (WGS) data from 2,658 cancer patients across 38 different primary sites1. WGS is able to document the quantity and distribution telomeric repeats2. In one papers analyzing dataset, Sieverling et al.3 confirmed previous data4 indicating that tumors with truncating ATRX or DAXX alterations, referred as ATRX/DAXXtrunc, have aberrant telomere variant repeat (TVR) distribution. By regarding these mutations, vs. TERT modifications (TERTmod; i.e. promoter mutations +/? amplifications structural variations), indicators Alternative Lengthening Telomeres (ALT) telomerase, they built a random forest classifier for ALT-probability, then associated genomic characteristics putative Telomere Maintenance Mechanism (TMM)3. However, we show here equating ATRX/DAXXtrunc TERTmod ALT respectively, results in TMM predictions which correlate poorly assay data. are heterogeneously distributed ALT-positive (ALT+) types, telomerase-positive tumors4. Although strongly TMM, most do not harbor them, making them inadequate basis building large-scale pan-cancer study4–7. Here, provide new analysis data, based on C-circle (CCA)8 available subset tumors4,9,10. We al. score overestimates proportion misclassifies when absent. also some TVR regardless TMM. Finally, propose identify cohort.