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Clinical Trial
. 2014 Mar 13;9(3):e91031.
doi: 10.1371/journal.pone.0091031. eCollection 2014.

Deregulation of COMMD1 is associated with poor prognosis in diffuse large B-cell lymphoma

Minna Taskinen  1 , Riku Louhimo  2 , Satu Koivula  1 , Ping Chen  2 , Ville Rantanen  2 , Harald Holte  3 , Jan Delabie  4 , Marja-Liisa Karjalainen-Lindsberg  5 , Magnus Björkholm  6 , Øystein Fluge  7 , Lars Møller Pedersen  8 , Karin Fjordén  9 , Mats Jerkeman  9 , Mikael Eriksson  9 , Sampsa Hautaniemi  2 , Sirpa Leppä  1
Affiliations
Clinical Trial

Deregulation of COMMD1 is associated with poor prognosis in diffuse large B-cell lymphoma

Minna Taskinen et al. PLoS One. .

Abstract

Background: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL.

Methods: We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients.

Results: We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis.

Conclusion: COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL.

Trial registration: ClinicalTrials.gov NCT01502982.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Survival of DLBCL patients according to genomic aberrations.
PFS (A and C) and lymphoma-associated OS (B and D) rates according to indicated genomic aberration.
Figure 2
Figure 2. Expression of genes associated with amplifications in 2p15 and 18q12.2 locuses.
Boxes contain expression values between the 25th and 75th percentile in the tumour subgroup. The extremes denoted by asterisks represent maximum and minimum expression values.
Figure 3
Figure 3. PFS according to COMMD1 expression.
A. PFS according to exon array based COMMD1 expression values. B. PFS according to quantitative PCR analysis based COMMD1 expression values. In both A and B, the ideal cutoff values have been calculated using ROC curve analyses. In A the estimated area under the curve (AUC) was 0.717 (p = 0.063, 95% CI 0.531–0.903). In B the AUC was 0.759 (p = 0.062, 95% CI 0.468–1.000).
Figure 4
Figure 4. COMMD1 protein expression and outcome.
Representative examples of low (A) and high (B) expression levels of COMMD1 in FFPE DLBCL tissue (original magnifications 100×, and 400×). C–D. Outcome according to COMMD1 expression in the trial specific TMA cohort. PFS in in the whole TMA cohort (C) and in the GCB subgroup (D). E–F. Outcome according COMMD1 expression in the validation cohort. PFS in in the whole validation cohort (E) and in the GCB subgroup (F). The cutoff point (staining coverage of 8.9%) for survival outcomes (COMMD1 low vs high) was selected by the ROC curve analysis in the training set, and then applied also to validation cohort.
See this image and copyright information in PMC

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