Fig. 2: Atypical TERTp mutations arise at pre-existing or de novo-formed UV hotspot positions.

a Mutation frequencies in a 80 bp region of the TERTp (chr5:1295188−1295268, hg19) in highly TERTp-mutated ( ≥ 20% of samples) GENIE cancer types, which were further subdivided into non-UV associated (“High TERTp, no UV”) or UV-associated (“High TERTp, UV”) subcohorts as indicated in Fig. 1. Mutations at a native (preexisting) ETS factor binding site arise only in the UV-exposed set, at positions in the ETS motif known to exhibit a UV damage hotspot effect when occupied (primarily CCTTCCK but also CCTTCCK). The schematic shows GABP binding to mutant TERTp sequences. b Frequencies in the UV-exposed subcohort following further subdivision of tumours by presence (positive axis) or absence (negative axis) of a TERTp driver mutation (−124, −126 or −139/−138 bp). Nearly all native ETS site mutations co-exist with primary driver events in the same patients, suggestive of a two-step model. Inset shows contingency table for driver and native site mutation co-occurrence (P-value from two-sided Fisher’s exact test). Equally, atypical mutations at −149 and −126 bp, predicted secondary hotspot bases at de novo ETS sites from −146 and −124 bp driver SNVs, co-exist with driver events. SNV, single nucleotide variant; DNV, double nucleotide variant; ONV, oligonucleotide variant; CPD, cyclobutane pyrimidine dimer. Source data are provided as a Source Data file.