Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma

Abstract

T-cell non-Hodgkin’s lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin’s lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), 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 Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin’s T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma.

Genome-wide mutational signatures of immunological diversification in normal lymphocytes

“…SBS7 is the canonical signature of ultraviolet light damage, the predominant mutational process in melanoma (28), normal skin (18,29) and mycosis fungoides (30,31), a T-cell lymphoma derived from skin-resident memory T cells (32). The signature we extracted in memory lymphocytes matches the features of SBS7, with a predominance of C>T substitutions in a dipyrimidine context, transcriptional strand bias and a high rate of CC>TT dinucleotide substitutions (Fig.…”

Targeted Deep Sequencing of Mycosis Fungoides Reveals Intracellular Signaling Pathways Associated with Aggressiveness and Large Cell Transformation

“…As a representative example, data on the mutational profile of patient #1 are illustrated in Figure 2 . The occurring mutations constitute C > T or CC > TT transitions indicating a typical UV signature [ 23 , 24 ]. The depicted findings elucidate the complex genomic pattern of repetitive biopsies obtained from patient #1.…”

The Microenvironment’s Role in Mycosis Fungoides and Sézary Syndrome: From Progression to Therapeutic Implications

“…The role of the microenvironment in MF progression is fascinating. Indeed, apart from genetic mutations [174][175][176], one alternative player involved in the progression from early to advanced lesions, the microenvironment may play a crucial role in MF and SS progression. Overall, microenvironment changes lead to immunosuppression given the presence of immature APCs or by the recruitment of immunosuppressive cells.…”