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. 2015 Sep;47(9):1011-9.
doi: 10.1038/ng.3356. Epub 2015 Jul 20.

Genomic landscape of cutaneous T cell lymphoma

Jaehyuk Choi  1   2 , Gerald Goh  3   4 , Trent Walradt  1 , Bok S Hong  1 , Christopher G Bunick  1 , Kan Chen  1 , Robert D Bjornson  5 , Yaakov Maman  3   6 , Tiffany Wang  1 , Jesse Tordoff  1 , Kacie Carlson  1 , John D Overton  7 , Kristina J Liu  1 , Julia M Lewis  1 , Lesley Devine  8 , Lisa Barbarotta  9 , Francine M Foss  1   9 , Antonio Subtil  1 , Eric C Vonderheid  10 , Richard L Edelson  1 , David G Schatz  3   6 , Titus J Boggon  11 , Michael Girardi  1 , Richard P Lifton  3   4   12
Affiliations

Genomic landscape of cutaneous T cell lymphoma

Jaehyuk Choi et al. Nat Genet. 2015 Sep.

Abstract

Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NF-κB signaling, chromatin remodeling and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations (mean of 11.8 pathogenic SCNVs versus 1.0 somatic single-nucleotide variant per CTCL). These findings have implications for new therapeutics.

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Figures

Figure 1
Figure 1. Landscape of somatic alterations in CTCL
Each column shows data for one CTCL. (a) The number of SSNVs in each CTCL along with the relative frequency of transitions and transversions is shown. (b) Select significant somatic alterations identified by whole exome sequencing are shown. Genes above the solid horizontal line have significant support for gene localizing mutations. Genes shown below the solid horizontal line represent putative driver genes residing on significant narrow focal SCNVs (< 10 genes in GISTIC interval). * indicates a Q-value between 0.1 and 0.25 supporting the specific gene indicated. (c) Composite plot of somatic copy number abnormalities. Listed are select implicated driver genes.
Figure 2
Figure 2. Recurrent mutations in CTCL
(a) Schematic of SSNVs in CD28, RHOA, PLCG1, and NFKB2. (b) Structural model of CD28-CD86 complex highlighting p.Phe51 and p.Gln77 (red spheres). CD28 coordinates (PDB ID: 1YJD; dark blue) were superimposed on the CTLA-4-CD86 complex (magenta; PDB ID: 1I85). Insets show electrostatic interactions at the indicated amino acids. (c) Locations of p.Phe51 on CD28 (PDB ID: 1YJD; blue) and p.Val69 on CTLA-4 (PDB ID: 1I8L; grey) crystal structures. p.Phe51 and p.Val69 were highlighted red. (d) p.Phe51 on CD28 and p.Val69 on CTLA-4 are highly conserved. E, F, R, and V denote glutamate, phenylalanine, arginine, and valine, respectively. (e–f) Binding of CD86-Fc to 293T cells stably transduced with human wild-type (WT) CD28, (e) CD28 (p.Phe51Val), or (f) CD28 (p.Gln77Pro). CD86-Fc binding was detected by a fluorescently labeled antibody. Fluorescence was then normalized based on the relative surface expression of the CD28 isoform for each sample. Normalized mean fluorescence intensity (MFI) with standard error of seven independent experiments were plotted as a function of CD86-Fc concentration. (g) IL-2 production from Jurkat cells transduced with WT CD28 or CD28 (p.Phe51Val). Jurkat cells were stimulated with phorbol myristate acetate (50 ng/ml), ionomycin (1 μg/ml), and the indicated concentrations of CD86-Fc for 6 hours. Relative IL-2 transcript levels were determined by quantitative RT-PCR, using GAPDH as a control. Graphs plot the means and standard error of 5 biological replicates. Statistical significance was assessed for by two-sided paired ratio t-test (e–g).* P<0.05. ** P<0.005. *** P<0.0005.
Figure 3
Figure 3. Localizing mutations and RNA transcript levels in CTCL
(a) Schematics of SSNVs in ARID1A, DNMT3A, FAS, and ZEB1. (b) Composite plots of deletions across chromosome 1, 2, and 10 with a magnified view of SCNVs at 1p36.11, 2p23.3, and 10p11.22, respectively. Red boxes define minimal common regions (MCR) shared by all SCNVs at each locus. (c–d) Histogram of gene-localizing mutations within the GISTIC confidence interval at 2p23.3 and 10p11.22. Gene-localizing mutations include SSNVs and focal SCNVs that include at least one gene but not all of the genes in the interval. ** likelihood ratio > 1,000:1 supporting one gene as the driver gene in the interval. * genes immediately outside the GISTIC intervals. (e) Increased levels of GATA-3 with ZEB1 knockdown in PMA and Ionomycin (PMA/Ion) stimulated Jurkat cells. Representative experiment of 3 biological replicates is shown. (f) Expression of genes is altered by deletion and amplification. The transcript levels (fragments per kilobase per million reads) of all genes when diploid was normalized to a Z-score of zero with a standard deviation of 1. Mean and standard errors for the transcript levels of the same genes when heterozygously deleted or amplified are shown. (g) Z-scores of putative driver genes with at least 3 CTCLs diploid for the indicated gene. For (f) and (g), statistical significance was calculated using the chi-square test testing the null hypothesis that deleted or amplified genes’ transcript levels are equally likely to be higher or lower than the mean transcript level when the gene is diploid.
Figure 4
Figure 4. Contribution of SCNVs to CTCL
(a) Ratio of deletions: SSNVs in CTCL compared to other cancer-types for TP53 and DNMT3A. (b) Ratio of significant focal deletions to significant SSNVs + significant focal amplifications for driver mutations in CTCL compared to all cancers with available data from the TCGA. All cancers are annotated with the abbreviations assigned by the TCGA. (c) Number of CTCLs with complex genomic rearrangements at each chromosome. (d–e) CIRCOS plots and magnified views of structural rearrangements in two CTCLs. In the CIRCOS plots, blue lines represent interchromosomal translocations. Red lines represent intrachromosomal rearrangements. In the magnified views of individual structural variants, each arrow represents a chromosomal segment with the arrowhead indicating the direction of increasing nucleotide position number (hg18). The numbers bordering each arrow reflects the nucleotide positions of each contiguous genomic segment. The colors of the arrows reflect the chromosome from which it is derived. The reference chromosome is the wild-type chromosome. The dotted line in the reference chromosome represents regions of genomic loss in CTCL. Subject chromosomes reflect the rearranged chromosome in the CTCL sample. (f) High-scoring heptamers are enriched in the 55 bp windows at the breakpoints in CTCLs vs. epithelial cancers. High-scoring heptamers were defined as heptamers that are highly homologous to consensus RAG cleavage sites (RSS-score >8.55; Methods). * P-value<0.05, one-sided Fisher’s exact test. (g) High-scoring heptamers are present within 5 bp of the breakpoints underlying the C-terminal NFKB2 truncation in sample 17. The high-scoring heptamers are underlined.
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