Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma

Sci Rep. 2021 Feb 17;11(1):3962. doi: 10.1038/s41598-021-83352-4.

Abstract

T-cell non-Hodgkin's lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin's lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin's T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / metabolism
  • Databases, Genetic
  • Humans
  • Interferon Regulatory Factors
  • Lymphoma, T-Cell / etiology
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / metabolism
  • Lymphoma, T-Cell / pathology
  • Lymphoma, T-Cell, Cutaneous / etiology*
  • Lymphoma, T-Cell, Cutaneous / genetics*
  • Lymphoma, T-Cell, Cutaneous / pathology
  • Mutation / genetics
  • Sezary Syndrome / blood
  • Skin Neoplasms / pathology
  • Ultraviolet Rays / adverse effects*

Substances

  • Interferon Regulatory Factors
  • interferon regulatory factor-4