Mechanistic basis of atypical TERT promoter 1 mutations

Non-coding mutations in the TERT promoter (TERTp), typically at one of two bases -124 and-146 bp upstream of the start codon, are among the most prevalent driver mutations in humancancer. Several additional recurrent TERTp mutations have been reported, particularly in skincancers, but their functions and origins remain unexplained. Here, we show that atypical TERTpmutations arise secondary to canonical TERTp mutations in a two-step process. CanonicalTERTp mutations create de novo binding sites for ETS family transcription factors that inducefavourable conditions for DNA damage formation by UV light, thus creating a hotspot effectbut only after a first mutational hit. In agreement, atypical TERTp mutations occur in tandemwith the canonical mutations in large cancer cohorts and arise subclonally specifically on theTERTp driver mutant chromosome homolog of melanoma cells treated with UV light in vitro.Our study gives an in-depth view of TERTp mutations in cancer and provides a mechanisticexplanation for atypical TERTp mutations.