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Dryad

Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in mycosis fungoides and Sezary syndrome

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Dec 10, 2019 version files 2.19 MB

Abstract

T-cell non-Hodgkin’s lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of mutational catalogues derived from whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin’s lymphoma to identify mutational signatures and recurrent gene mutations associated with specific causal peaks within these signatures. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphoma subtypes, reflecting the derivation of these malignancies from memory T-cell subsets. The majority of the recurrent driver gene mutations identified across different types of T-cell lymphomas were unique to malignancies of haematopoietic and lymphoid origin and influenced T-cell signalling pathways.  Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to strongly correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. The recurrent STAT3 Y640F mutation found in different T-cell lymphomas was significantly associated with signature 5.  Signature 7, implicating UV exposure as a potential initiating factor was uniquely identified in cutaneous T-cell lymphoma, 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 74% of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through both skin and blood and strongly implicating a role for UV in the pathogenesis of cutaneous T-cell lymphoma.