Sezary Syndrome (SS)

Overview

Sézary syndrome (SS) is an aggressive leukemic form of cutaneous T-cell lymphoma (CTCL), defined by circulating malignant CD4+ T cells with cerebriform nuclei (Sézary cells) in the peripheral blood, erythroderma, and lymphadenopathy. It sits within the Mature T and NK Neoplasms (MTNN) branch of OncoTree (parent: MTNN; formerly coded SEZS). Genomically it is characterized by a high burden of somatic copy-number alterations, recurrent deletions of multiple tumor suppressors (TP53, RB1, PTEN, DNMT3A, CDKN1B), and somatic mutations in epigenetic regulators and TCR/NFκB/NFAT signaling genes.

Cohorts in the corpus

  • ctcl_columbia_2015 — whole-exome sequencing of 25 Sézary syndrome tumor-normal pairs (peripheral-blood CD4+ T cells as tumor; granulocytes or buccal swab as germline) among 42 CTCL patients profiled PMID:26551667.

Recurrent alterations

  • Whole-exome sequencing of 25 Sézary syndrome cases yielded a median of 39 non-synonymous somatic mutations/sample (range 1–182) and a median of 21 copy-number alterations/sample (range 0–56) PMID:26551667.
  • Recurrent chromosomal deletions: TP53 17p13.1 (13/25; 52%), PTEN 10q23.3 (5/25; 20%), DNMT3A 2p23.3 (5/25; 20%, including 2 homozygous), CDKN1B 12p13.1 (5/25; 20%), RB1 13q14.2 (4/25; 16%); recurrent gains at 8q (13/25; 52%) and chromosome 7 (5/25; 20%) PMID:26551667.
  • Epigenetic regulator mutations: TET2 (p.Gln1654, p.Cys1932Phe, p.Gln649), CREBBP (p.Gln839*, p.Ser1207fs), KMT2C p.Thr3941fs, BRD9 p.Gln479His/p.His467_Leu468del, SMARCA4 p.Ser1238Tyr, CHD3 p.Gln660His/p.Ser230Leu PMID:26551667.
  • TCR/NFκB signaling mutations: CARD11 linker-domain p.Ser615Phe and p.Glu626Lys (NFκB-activating, validated functionally), TNFRSF1B p.Gly256Cys/p.Thr377Ile, PLCG1 p.Gly722Val/p.Arg48Trp/p.Glu1163Lys, PRKG1 p.Glu17Lys/p.Arg21Gln (cGKIβ LoF, validated to enhance NFAT signaling), JAK3 p.Val678Leu PMID:26551667.
  • PREX2 p.Arg297Cys and p.Glu1295Lys (PTEN-inhibitory Rac-GEF; alleles also reported in melanoma and head-and-neck cancer) PMID:26551667.
  • SS (n=10) was genomically distinct with the fewest SCNAs and mutations of any histology; all 10 cases carried SS18-SSX1 or SS18-SSX2 t(X;18) fusions; iCluster placed all SS in C4 (high FGFR3, miR-183, PDE4A promoter methylation, partial/complete 3p loss in 5/10 cases) PMID:29100075

Subtypes

  • Sézary syndrome and mycosis fungoides constitute the two dominant CTCL subtypes in the da Silva Almeida et al. cohort; Sézary syndrome has markedly higher CNA burden (median 21 vs 1) and is dominated by tumor suppressor deletions, whereas mycosis fungoides shows more MAPK1/STAT3 point mutations PMID:26551667.

Therapeutic landscape

  • Broad CTCL cell-line sensitivity to bortezomib and Mi-2 (NFκB inhibitor) across HH, HUT78, HUT102, SeAX lines regardless of genotype, reflecting convergent NFκB activation from multiple mutational routes (CARD11, TNFRSF1B, PRKG1 LoF) PMID:26551667.
  • tofacitinib and ruxolitinib (JAK inhibitors) selectively active in JAK3 p.Ala573Val-mutant HUT78; authors propose stratifying CTCL patients by JAK3/STAT3/SH2B3 genotype for JAK-inhibitor trials PMID:26551667.
  • MEK1/2 inhibition (U0126) and NFAT inhibition (FK506) showed only modest antitumor effects despite recurrent MAPK1/BRAF/PRKG1 mutations, suggesting combination strategies may be needed PMID:26551667.

Sources

  • PMID:26551667 — da Silva Almeida et al., whole-exome sequencing of 42 CTCL patients (25 Sézary syndrome, 8 mycosis fungoides).

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