A Pan-Cancer Study of Somatic TERT Promoter Mutations and Amplification in 30,773 Tumors Profiled By Clinical Genomic Sequencing

Promoter mutations involving the TERT gene have been identified in multiple cancer types. Other TERT alterations remain poorly characterized. Sequencing data from 30,773 tumors analyzed by a hybridization capture next-generation sequencing assay (MSK- IMPACT) was analyzed for the presence of TERT alterations. Promoter rearrangements (500 bases upstream of the transcriptional start site), hypermethylation (n=57) and gene expression (n=155) was evaluated for a subset of cases. We identified mutually exclusive and recurrent promoter mutations at 3 hotspots upstream of the transcriptional start site in 11.3% of cases (-124: 74%; -146: 24%; -136: <2%). Mutually exclusive amplification events were identified in another 2.3% of cases, while mutually exclusive rearrangements proximal to the TERT gene were seen in 24 cases. The highest incidence of TERT promoter mutations was seen in cutaneous melanoma (82%), while amplification events significantly outnumbered promoter mutations in well differentiated/ dedifferentiated liposarcoma (14.1% vs 2.4%) and adrenocortical carcinoma (13.6% vs 4.5%). Gene expression analysis suggests that the highest levels of gene expression are seen in cases with amplifications and rearrangements. Hypermethylation events upstream of the TERT coding sequence were not found to be mutually exclusive with known pathogenic alterations. Future studies aimed at defining the prevalence and prognostic impact of TERT alterations should attempt to incorporate other pathogenic TERT alterations as these might significantly impact telomerase function.