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. 2012 Jan;132(1):188-97.
doi: 10.1038/jid.2011.254. Epub 2011 Sep 1.

Characterization of the DNA copy-number genome in the blood of cutaneous T-cell lymphoma patients

William M Lin  1 , Julia M Lewis, Renata B Filler, Badri G Modi, Kacie R Carlson, Swapna Reddy, Adam Thornberg, Gordon Saksena, Sheila Umlauf, Patrick A Oberholzer, Maria Karpova, Gad Getz, Shrikant Mane, Levi A Garraway, Reinhard Dummer, Carole L Berger, Richard L Edelson, Michael Girardi
Affiliations

Characterization of the DNA copy-number genome in the blood of cutaneous T-cell lymphoma patients

William M Lin et al. J Invest Dermatol. 2012 Jan.

Abstract

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin's lymphoma that may variably involve the skin, lymph nodes, and peripheral blood. Malignant burden ranges from cutaneous patches and plaques with little evidence of blood involvement to erythroderma often in association with frank leukemia, as in Sézary syndrome. Toward a better understanding of the pathogenesis of this CD4+ T-cell malignancy, we conducted a high-resolution genomic analysis combining DNA (23 samples) and mRNA (12 samples) data of peripheral blood isolates from CTCL patients across a spectrum of stages. Strikingly, even patients with limited involvement, e.g., normal CD4 counts, contained significant copy-number alterations. Defining genomic characteristics of CTCL blood involvement included gains on 8q and 17q, and deletions on 17p and chromosome 10. A consensus analysis of 108 leukemic CTCL samples demonstrated global similarities among patients with varied blood involvement, narrowing 38 of 62 loci. Toward an annotated framework for in vitro testing, we also characterized genomic alterations in five CTCL cell lines (HH, HUT78, PNO, SeAx, and Sez4), revealing intact core features of leukemic CTCL. Together, these studies produce the most comprehensive view of the leukemic CTCL genome to date, with implications for pathogenesis, molecular classification, and potential future therapeutic developments.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors state no conflict of interest.

Figures

Figure 1
Figure 1. Significant DNA copy-number alterations in leukemic cutaneous T-cell lymphoma (CTCL)
Statistically significant (a) amplifications and (b) deletions pinpointed by GISTIC (Genomic Identification of Significant Targets in Cancer) aggregate analysis of 23 CTCL patient samples. Chromosomal location is across the bottom with labeled cytobands corresponding to the center of the region and cancer-related genes from Beroukhim et al. (2010), or known CTCL genes labeled above the region. *A gene adjacent to the peak region. Significance reported as false discovery rate–corrected q-value.
Figure 2
Figure 2. Consensus analysis of the leukemic cutaneous T-cell lymphoma (CTCL) genome
Analyzing seven CTCL genomic studies (Mao et al., 2002, 2003; Fischer et al., 2004; Vermeer et al., 2008; Caprini et al., 2009; Laharanne et al., 2010), including our own, common regions of amplification (shown in red) and deletion (shown in blue) were defined by at least two studies and the minimal common region was determined by at least one study. The first column indicates the chromosome number. The second column indicates the number of studies including the minimal common region. Cancer-related genes from Beroukhim et al. (2010) are shown in the final column.
Figure 3
Figure 3. 17q25.1 amplification candidate targets
(a) Unsupervised analysis of significant copy-number (CN) mutations in cutaneous T-cell lymphoma (CTCL) as defined by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis was performed with hierarchical clustering. Each patient’s skin disease severity after 1 year of treatment is annotated next to the sample number. (b) Fisher’s exact test showed 17q25.1 amplification to be more common in patients with stable/worsened skin disease after 1 year of treatment; however, this was not significant after Bonferroni multiple-hypothesis correction. (c) Using Comparative Marker Selection, differential expression analysis of samples with 17q25.1 amplification versus no amplification reveals candidate targets that are amplified and overexpressed in the data set of Caprini et al. (2009; shown in red), our data set (shown in blue), and the overlap (shown in purple).
Figure 4
Figure 4. Genomic alterations in leukemic cutaneous T-cell lymphoma (CTCL) cell lines
A heatmap view shows the presence of amplifications and deletions in five cell lines derived from Sézary syndrome patients. The heatmap is sorted by the number of cell lines affected, ranging from 0 to 4. Genetic alterations and q-values are derived from a combined GISTIC (Genomic Identification of Significant Targets in Cancer) run of 5 cell lines and 23 leukemic CTCL patient samples. Genetic alterations are listed by the cytoband in the middle of each region and regions in italics were found in the meta-analysis.
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