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

Science. 2022 Nov 11;378(6620):664-668. doi: 10.1126/science.abq0607. Epub 2022 Nov 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Melanoma* / genetics
  • Mutation
  • Promoter Regions, Genetic* / genetics
  • Shelterin Complex* / genetics
  • Skin Neoplasms* / genetics
  • Telomerase* / genetics
  • Telomere / genetics
  • Telomere / metabolism
  • Telomere Homeostasis* / genetics
  • Telomere-Binding Proteins* / genetics
  • Transcriptional Activation

Substances

  • ACD protein, human
  • Shelterin Complex
  • Telomerase
  • Telomere-Binding Proteins
  • TERT protein, human