Cutaneous T-Cell Lymphoma — Columbia 2015

Overview

Whole-exome sequencing of 42 tumor-normal pairs from cutaneous T-cell lymphoma (CTCL) patients — 25 Sézary syndrome (SS) and 17 other CTCL including 8 mycosis fungoides (MYCF) — collected across Northwestern University (Chicago) and Leiden University Medical Center. Raw data deposited in dbGaP under accession phs000994.v1.p1. Reference genome hg19.

Composition

  • 25 Sézary syndrome samples: peripheral-blood CD4+ T cells as tumor; granulocytes or buccal swab as matched normal.
  • 17 other CTCL samples (8 mycosis fungoides, 9 other CTCL): skin biopsies as tumor; buccal swab as normal.
  • Cancer types: SS (Sézary syndrome), MYCF (mycosis fungoides).
  • Agilent SureSelect 50 Mb All Exon kit; Illumina HiSeq2000, paired-end 2×100 bp; mean depth 143.5×, 95.3% of targets covered >30×.
  • Copy-number analysis: EXCAVATOR (pooled or somatic mode).
  • Variant calling: SAVI Bayesian framework; somatic variants retained at ≥15% VAF, absent in normal.

Assays / panels (linked)

Papers using this cohort

  • PMID:26551667 — da Silva Almeida et al. 2015, “The mutational landscape of cutaneous T-cell lymphoma and Sézary syndrome,” Nature Genetics.

Notable findings derived from this cohort

  • Sézary syndrome dominated by chromosomal deletions of tumor suppressors: TP53 17p13.1 (52%), PTEN 10q23.3 (20%), CDKN1B 12p13.1 (20%), RB1 13q14.2 (16%), and DNMT3A 2p23.3 (20%, including two homozygous deletions) PMID:26551667.
  • Recurrent mutations in epigenetic regulators: TET2, CREBBP, KMT2D, KMT2C, BRD9, SMARCA4, CHD3 in Sézary syndrome; SMARCA4 and KMT2D/KMT2C in mycosis fungoides PMID:26551667.
  • TCR-signaling effector mutations activating MAPK, NFkB, and NFAT pathways: MAPK1 p.E322K/A (mycosis fungoides), BRAF p.K601E, CARD11 linker-domain mutations (p.S615F, p.E626K) as NFkB activators, PRKG1 N-terminal LoF mutations, JAK3 p.V678L with SH2B3 LoF PMID:26551667.
  • Median 39 non-synonymous somatic mutations per Sézary syndrome sample; median 21 CNAs per sample (range 0–56) PMID:26551667.
  • Three mutational signatures in Sézary syndrome: C>T at NpCpG (CpG deamination/aging), C>A at CpCpN, and C>T at CpCpN/TpCpN PMID:26551667.
  • CTCL cell lines (HH, HUT78, HUT102, SeAX) broadly sensitive to NFkB inhibition (Mi-2, bortezomib); JAK3-mutant HUT78 line responsive to tofacitinib and ruxolitinib PMID:26551667.

Sources

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