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Independent Loss of Methylthioadenosine Phosphorylase (MTAP) in Primary Cutaneous T-Cell Lymphoma

Wesley J Woollard1, Nithyha P Kalaivani1, Christine L Jones1

  • 1St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.

The Journal of Investigative Dermatology
|February 14, 2016
PubMed

Insights

Methylthioadenosine phosphorylase (MTAP) deletion is common in cutaneous T-cell lymphoma, particularly early-stage mycosis fungoides (MF). This loss occurs independently of CDKN2A, suggesting a specific role for MTAP in MF development.

Area of Science:

  • Oncology
  • Genetics
  • Dermatology

Background:

  • Methylthioadenosine phosphorylase (MTAP) and tumor suppressor genes CDKN2A-CDKN2B are frequently deleted in cancers.
  • The role of MTAP in mycosis fungoides (MF) and Sézary syndrome (SS), subtypes of cutaneous T-cell lymphoma (CTCL), is not well understood.

Purpose of the Study:

  • To investigate the frequency and significance of MTAP deletions in MF and SS.
  • To explore the relationship between MTAP and CDKN2A deletions in CTCL.
  • To identify potential mechanisms of MTAP inactivation in CTCL.

Main Methods:

  • Quantitative reverse transcription PCR was used to assess MTAP and CDKN2A copy number loss in 213 skin samples from MF/SS patients.
  • Deep sequencing and read-depth analysis were performed on peripheral blood mononuclear cell DNA from SS patients.
  • MTAP mRNA expression was analyzed in CD4+ cells from SS patients.
  • Promoter hypermethylation was investigated in a CTCL cell line.

Main Results:

  • MTAP copy number loss (34%) was more frequent than CDKN2A loss (12%) across all CTCL stages in skin samples.
  • In early-stage MF, MTAP loss occurred independently of CDKN2A loss in 37% of samples.
  • In SS, MTAP loss was uncommon alone but occurred with CDKN2A deletion in 18% of peripheral blood mononuclear cells.
  • Reduced MTAP mRNA expression in SS CD4+ cells correlated with copy number loss but also occurred without it.
  • No nonsynonymous mutations in MTAP/CDKN2A-CDKN2B were found in SS, but focal deletions were suggested.
  • Promoter hypermethylation was identified as a mechanism for MTAP downregulation in a CTCL cell line.

Conclusions:

  • MTAP deletion is a frequent event in CTCL, especially in early-stage MF, and can occur independently of CDKN2A loss.
  • These findings suggest a potential selection for MTAP deletion in the tumor microenvironment during early MF development.
  • Mechanisms like promoter hypermethylation may contribute to MTAP inactivation in CTCL.

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