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

Pattra Chun-O, Angela M. Hinchie, Holly C. Beale, Agustin A.Gil Silva, Elizabeth Rush, Cindy Sander, Carla J. Connelly, Brittani K.N. Seynnaeve, John M. Kirkwood, Olena M. Vaske, Carol W. Greider, Jonathan K. Alder

Research output: Contribution to journalArticlepeer-review

Abstract

Overcoming replicative senescence is an essential step during oncogenesis, and the reactivation of TERT through promoter mutations is a common mechanism. TERT 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 ACD encoding the shelterin component TPP1. ACD promoter variants are present in about 5% of cutaneous melanoma and co-occur with TERT 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 TERT promoter. The variants increase the expression of TPP1 and function together with TERT to synergistically lengthen telomeres. Our findings suggest that TPP1 promoter variants collaborate with TERT activation to enhance telomere maintenance and immortalization in melanoma.

Original languageEnglish (US)
Pages (from-to)664-668
Number of pages5
JournalScience
Volume378
Issue number6620
DOIs
StatePublished - Nov 11 2022

ASJC Scopus subject areas

  • General

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