Abstract
Sézary syndrome (SS) is a genetically and clinically distinct entity among cutaneous T-cell lymphomas (CTCL). SS is characterized by more aggressive disease compared to the most common indolent type of CTCL, mycosis fungoides. However, there are limited available genomic data regarding SS. To characterize and expand current mappings of the genomic landscape of CTCL, whole exome sequencing (WES) was performed on peripheral blood samples from seven patients with SS. We detected 21,784 variants, of which 21,140 were novel and 644 were previously described. Filtering revealed 551 nonsynonymous variants among 525 mutated genes−25 recurrent mutations and 1 recurrent variant. Several recurrently mutated genes crucial to pathogenesis pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT), peroxisome proliferator-activated receptors (PPAR), PI3K-serine/threonine protein kinases (AKT), and fibroblast growth factor receptors (FGFR), were identified. Furthermore, genetic mutations spanned both known and novel genes, supporting the idea of a long-tail distribution of mutations in lymphoma. Acknowledging these genetic variants and their affected pathways may inspire future targeted therapies. WES of a limited number of SS patients revealed both novel findings and corroborated complexities of the “long-tail” distribution of previously reported mutations.
Highlights
Cutaneous T-cell lymphoma (CTCL) consists of a rare heterogeneous group of clonal T-cell lymphoproliferative disorders, including mycosis fungoides (MF) and Sézary syndrome (SS)
This study identified 55 putative driver genes and implicated 17 novel gene mutations involving pathways that affect chromatin remodeling (BCOR, KDM6A, SMARCB1, TRRAP), immune surveillance (CD58, RFXAP), MAPK signaling (MAP2K1, NF1), NF-κB signaling (PRKCB, CSNK1A1), PI-3-kinase signaling (PIK3R1, VAV1), RHOA/cytoskeleton remodeling (ARHGEF3), RNA splicing (U2AF1), T-cell receptor signaling (PTPRN2, RLTPR), and T-cell differentiation (RARA) [7]
whole exome sequencing (WES) analyses were used to elucidate the molecular biology of SS and its genomic landscape
Summary
Cutaneous T-cell lymphoma (CTCL) consists of a rare heterogeneous group of clonal T-cell lymphoproliferative disorders, including mycosis fungoides (MF) and Sézary syndrome (SS). Sézary Syndrome Mutations of cytokine pathways, and the inhibition of P53 accounts for the increased cell proliferation and leukemic behavior observed in patients with this disease [3, 4]. WES analyses of 42 CTCL cases, including 25 SS and 8 MF cases, showed highly prevalent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressors, which broadly implicates epigenetic regulation and signaling [5]. Single gene alterations, and copy number alterations in SS represent genomic diversity involving multiple pathways, such as T-cell receptor signaling, NF-kB and JAK/STAT pathways, apoptosis control, chromatin remodeling, and DNA damage response [8]. The clinical heterogeneity of MF and SS cannot be solely explained by known mutations
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