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 <i>TERT</i> through promoter mutations is a common mechanism. <i>TERT</i> 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 <i>ACD</i> encoding the shelterin component TPP1. <i>ACD</i> promoter variants are present in about 5% of cutaneous melanoma and co-occur with <i>TERT</i> 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 <i>TERT</i> promoter. The variants increase the expression of <i>TPP1</i> and function together with TERT to synergistically lengthen telomeres. Our findings suggest that <i>TPP1</i> promoter variants collaborate with <i>TERT</i> activation to enhance telomere maintenance and immortalization in melanoma.