Transcriptional profiles predict disease outcome in patients with cutaneous T-cell lymphoma

Abstract

Purpose: Average survival of cutaneous T-cell lymphoma (CTCL) is associated with clinical stage at diagnosis, where stage I has a favorable survival prognosis, whereas patients with more advanced stages succumb to their disease within 5 years. Although the majority of patients present with an early-stage CTCL, 15% to 20% of them will inevitably progress. Current state-of-the-art clinical criteria cannot identify individuals with stage I disease who are at risk of progression. The purpose of the current work is to gain novel molecular insight into the pathophysiology of CTCL to be able to identify patients with poor versus favorable prognosis. Our previous work used microarray analysis of skin biopsies from 62 CTCL patients to perform an unsupervised analysis of gene expression, which revealed three distinct transcription profile clusters.

Experimental design: In the present study, we used reverse transcription-PCR to confirm gene expression levels for a subset of representative genes in each cluster. We also performed a Kaplan-Meier analysis of survival and disease progression based on the 6 years of clinical follow-up.

Results: Our reverse transcription-PCR results confirmed the upregulation of representative genes for each cluster, whereas clinical analysis documents that all stage I cases that progressed to stage II and beyond were in poor and intermediate prognosis clusters 1 and 3 and none were in favorable prognosis cluster 2. This analysis also identified certain genes that were preferentially expressed in favorable (e.g., WIF-1) versus poor (e.g., IL-17F) prognosis clusters.

Conclusion: This work suggests that it may be possible to stratify CTCL patients into low-risk, intermediate-risk, and high-risk groups based on gene expression.

Figure 1

Validation of previous microarray results: RT-PCR Gene Expression Analysis in 62 CTCL patients. Quantitative RT-PCR expression of selected genes that were documented to be upregulated based on the previous microarray analysis in cluster 1 (A), cluster 2 (B) and cluster 3 (C) patients (10).

Figure 2

Kaplan-Meier Analysis of CTCL Patients A. CTCL Disease Progression, p=0.019 B. CTCL Survival, p=0.136 C. Progression of Patients with Stage I Disease, p=0.107.

Figure 3

Expression of molecular markers in Cluster 1–3 CTCL Patients. A. IL-17F marker is expressed in cluster 1 and 3 patients and is upregulated in a number of patients with progressive disease (*-progression, +-progression and death). B. WIF-1 is expressed in cluster 1 and 3 favorable prognosis patients (#-Stage I stable disease, *-progression). Patient M48: Diagnosed in 1998 with advanced disease. Progressed to Stage III in 2003 and to Stage IV in 2004. Currently doing well on appropriate therapy.