DOI: 10.5061/dryad.8cz8w9gkm
title: Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in mycosis fungoides and Sezary syndrome

description: 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.
description: On
 1<sup>st</sup> 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 <i>et. al.</i>
 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.