Related Experiment Video

Updated: Aug 15, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

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UV light-induced dual promoter mutations dismantle the telomeric guardrails in melanoma

Samantha L Sanford1, Patricia L Opresko2

  • 1Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USA; UPMC Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.

DNA Repair
|January 5, 2023
PubMed

Insights

Somatic variants in the TPP1 gene promoter act as a critical second hit in melanoma development. These UV-induced mutations cooperate with telomerase to enable telomere maintenance and melanoma cell immortalization.

Area of Science:

  • Oncology
  • Genetics
  • Dermatology

Background:

  • Melanoma progression from benign nevi requires mechanisms for telomere maintenance.
  • UV radiation is a primary driver of melanoma, causing mutations in genes like TERT.
  • Telomerase upregulation alone is insufficient for melanoma cell immortalization due to persistent telomere shortening.

Purpose of the Study:

  • To investigate additional genetic alterations enabling telomere maintenance in melanoma.
  • To identify novel genetic hits beyond TERT promoter mutations in melanoma development.

Main Methods:

  • Analysis of somatic variants in human melanoma genomes.
  • Examination of TPP1 gene promoter mutations and their functional consequences.
  • Assessment of TPP1 expression and its synergistic effect with telomerase on telomere length.

Main Results:

  • Somatic variants were identified in the promoter of the TPP1 gene in human melanomas.
  • These TPP1 promoter variants exhibit UV-induced DNA damage mutational signatures.
  • TPP1 promoter variants upregulate TPP1 expression, synergizing with telomerase to lengthen telomeres.

Conclusions:

  • TPP1 promoter variants represent a critical second hit in melanoma pathogenesis.
  • These variants contribute to telomere maintenance and melanoma cell immortalization.
  • Targeting TPP1 may offer new therapeutic strategies for melanoma treatment.
Keywords:
MelanomaPromoter mutationsTPP1TelomeraseTelomere biologyUV mutagenesis

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