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

T-cell non-Hodgkin's lymphomas (NHL) 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 NHL 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 NHL subtypes, reflecting the derivation of these malignancies from memory T-cell subsets. Adult T-cell leukemia-lymphoma (ATLL) was specifically associated with signature 17, which was found to strongly correlate with the IRF4 K59R mutation that is exclusive to ATLL. 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 blood 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.