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


Jones, Christine et al. (2020), Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in mycosis fungoides and Sezary syndrome, Dryad, Dataset,


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.


On 1st June 2017 Pubmed was searched using the terms ("Next Generation Sequencing"[All Fields] OR "Whole Exome Sequencing"[All Fields]) AND ("T cell lymphoma"[Tiab] OR "Mycosis Fungoides"[Tiab] OR "Sezary Syndrome"[Tiab] OR "T cell prolymphocytic leukaemia"[Tiab] OR "T cell large granular lymphocyte leukaemia"[Tiab] OR "Adult T cell leukemia/lymphoma"[Tiab] OR "CD30 positive T cell lymphoproliferative disorder"[Tiab]) NOT ("review"[Publication Type]) and Scopus was searched using the terms ( ( ALL ( "Next Generation Sequencing" )  OR  ALL ( "Whole Exome Sequencing" ) )  AND  ( TITLE-ABS-KEY ( "T cell lymphoma" )  OR  TITLE-ABS-KEY ( "Mycosis Fungoides" )  OR  TITLE-ABS-KEY ( "Sezary Syndrome" )  OR  TITLE-ABS-KEY ( "T cell prolymphocytic leukaemia" )  OR  TITLE-ABS-KEY ( "T cell large granular lymphocyte leukaemia" )  OR  TITLE-ABS-KEY ( "Adult T cell leukemia/lymphoma" )  OR  TITLE-ABS-KEY ( "CD30 positive T cell lymphoproliferative disorder" ) ) ) AND  ( LIMIT-TO ( DOCTYPE ,  "ar" )  OR  LIMIT-TO ( DOCTYPE ,  "le" ) ). The outputs were combined to identify 121 unique reports which were then manually curated to identify those which reported whole exome sequencing of mature T-cell lymphomas. Searches were also performed of various sequencing archives including NCBI Sequence Read Archive, NCBI dbGap, EMBL European Genome-phenome Archive and EMBL European Nucleotide Archive to check for any data which was not covered by the literature search.

In order to avoid skewing the analysis, we included only those studies where full mutation details were included in the published data and studies were excluded if they only listed driver mutations, or only listed genes which were mutated in more than one patient. We also only included samples where mutation calling was performed by comparison to a paired germline control to ensure the accuracy of mutation calling.

Choi et. al. only included a list of mutations in potential driver genes in their published work so their full mutation list was extracted from a data resource covering all the sequencing of cutaneous T-cell lymphoma. Mutations from the whole exome data of 403 patients were included in the analysis, a summary by study and disease subtype is provided in Table 1.

Mutation lists were extracted from the supplementary tables of the various studies and combined in R. Where the reference assembly was not hg19, co-ordinates were lifted over using the rtracklayer package. Finally, co-ordinates were sense checked using the GenomicRanges and BSgenome.Hsapiens.UCSC.hg19 packages to ensure that the listed reference base corresponded to the given location.