TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma.

Overcoming replicative senescence is an essential step during oncogenesis, and the reactivation of through promoter mutations is a common mechanism. promoter mutations are acquired in about 75% of melanomas but are not sufficient to maintain telomeres, suggesting that additional mutations are required. We identified a cluster of variants in the promoter of encoding the shelterin component TPP1. promoter variants are present in about 5% of cutaneous melanoma and co-occur with promoter mutations. The two most common somatic variants create or modify binding sites for E-twenty-six (ETS) transcription factors, similar to mutations in the promoter. The variants increase the expression of and function together with TERT to synergistically lengthen telomeres. Our findings suggest that promoter variants collaborate with activation to enhance telomere maintenance and immortalization in melanoma.