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Updated: Jun 10, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Published on: June 7, 2019

High frequency of p16(INK4A) promoter methylation in NRAS-mutated cutaneous melanoma

Anders Jonsson1, Rainer Tuominen, Eva Grafström

  • 1Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden.

The Journal of Investigative Dermatology
|August 13, 2010
PubMed

Insights

The p16(INK4A) tumor suppressor is frequently lost in melanoma. While promoter methylation and mutations contribute, other mechanisms also inactivate p16(INK4A), particularly in NRAS-mutated tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The p16(INK4A) tumor suppressor gene is frequently inactivated in malignant melanoma.
  • Understanding the mechanisms of p16(INK4A) loss is crucial for melanoma research.

Purpose of the Study:

  • To investigate the detailed mechanisms of p16(INK4A) inactivation in cutaneous melanoma metastases.
  • To correlate p16(INK4A) alterations with clinicopathological parameters and oncogene mutations.

Main Methods:

  • Analysis of 77 cutaneous melanoma metastases and 14 primary tumors.
  • Utilized methylation-specific PCR, direct sequencing, and immunohistochemistry for p16(INK4A) analysis.
  • Compared findings with NRAS and BRAF proto-oncogene mutation data.

Main Results:

  • p16(INK4A) promoter methylation occurred in 25% of metastases, with nonsynonymous mutations in 16%.
  • Protein expression was reduced in metastases compared to primary tumors (43% vs 71%).
  • Observed genetic/epigenetic alterations did not fully explain p16(INK4A) loss in 27 metastases, suggesting additional mechanisms.
  • p16(INK4A) promoter methylation was significantly associated with NRAS mutations (P=0.0004).

Conclusions:

  • Melanoma progression involves loss of p16(INK4A) expression through multiple genetic, epigenetic, and potentially other mechanisms.
  • NRAS mutations are linked to p16(INK4A) promoter methylation in melanoma.
  • Further research is needed to elucidate the complete spectrum of p16(INK4A) inactivation pathways in melanoma.

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