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

Christine L Jones,Vieri Grandi,Tracey J Mitchell,Serena Nik-Zainal,Sean J Whittaker,Tauanne D Amarante,Andrea Degasperi

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.

Highlights

Non-Hodgkin’s lymphomas (NHL) consist of distinct clinico-pathologic and molecular entities arising from nodal or extra-nodal s ites[1]
Cutaneous T-cell lymphomas, Sezary syndrome (SS) and mycosis fungoides (MF) variants, show an obvious clonotypic UV signature 7 associated with a high tumour mutational burden as expected for malignancies linked to a specific mutagen
The UV signature was identified in peripheral blood T-cells from 74% (67/90) of SS patients representing between 7.5 and 88% of the overall SNV mutational burden

Summary

Introduction

Non-Hodgkin’s lymphomas (NHL) consist of distinct clinico-pathologic and molecular entities arising from nodal or extra-nodal s ites[1]. As T-cell lymphomas are not included in TCGA, there have been no comprehensive studies of mutational signatures in T-cell NHL recent high-throughput sequencing studies have identified putative driver gene mutations targeting specific signalling pathways notably TCR, NF-kB and JAK-STAT s ignalling[10,11,12,13,14]. These findings suggest that some T-cell NHL are dependent on TCR signalling analogous to a dependence on BCR signalling in B-cell N HL15

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Conclusion