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 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.