Originally published as JCO Early Release 10.1200/JCO.2007.12.0410 on July 7 2008

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Five-Gene Model to Predict Survival in Mantle-Cell Lymphoma Using Frozen or Formalin-Fixed, Paraffin-Embedded Tissue

Elena Hartmann, Verònica Fernàndez, Victor Moreno, Joan Valls, Luis Hernández, Francesc Bosch, Pau Abrisqueta, Wolfram Klapper, Martin Dreyling, Eva Hoster, Hans Konrad Müller-Hermelink, German Ott, Andreas Rosenwald, Elías Campo

From the Institute of Pathology, University of Würzburg, Würzburg; Institute of Pathology, University of Kiel, Kiel; Department of Internal Medicine III, University of Munich, Munich, Germany; Hematopathology Section, Departments of Pathology and Hematology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona; and Unit of Biostatistics and Bioinformatics, Cancer Epidemiology Service, Institut Català d'Oncologia-Institut d'Investigació de Bellvitge, Barcelona, Spain

Corresponding author: Andreas Rosenwald, MD, Institute of Pathology, University of Würzburg; Josef-Schneider-Str 2, 97080 Würzburg, Germany; e-mail: rosenwald{at}mail.uni-wuerzburg.de

Purpose Despite the common underlying translocation t(11;14) involving cyclin D1 that is present in nearly all cases of mantle-cell lymphoma (MCL), the clinical course of the disease is highly variable. The aim of the present study was to develop a quantitative gene expression–based model to predict survival in newly diagnosed patients with MCL that involves a minimum number of genes and is applicable to fresh-frozen and formalin-fixed, paraffin-embedded (FFPE) tumor samples.

Patients and Methods The expression of 33 genes with potential prognostic and pathogenetic impact in MCL was analyzed using quantitative reverse-transcription polymerase chain reactions (qRT-PCR) in a low-density array format in frozen tumor samples from 73 patients with MCL. Multivariate Cox methods and stepwise algorithms were applied to build gene expression-based survival predictors. An optimized five-gene model was subsequently applied to FFPE tumor samples from 13 patients with MCL from the initial series and to 42 independent MCL samples.

Results The optimized survival predictor was composed of the five genes RAN, MYC, TNFRSF10B, POLE2, and SLC29A2 and was validated for application in FFPE tissue samples. It allowed the survival prediction of patients with MCL with widely disparate clinical outcome and was superior to the immunohistochemical marker Ki-67, an established prognostic factor in MCL.

Conclusion We here present a validated qRT-PCR–based test for survival prediction in patients with MCL that is applicable to fresh frozen as well as to FFPE tissue specimens. This test may prove useful to guide individualized treatment approaches for patients with MCL.

published online ahead of print at www.jco.org on July 7, 2008.

Supported by the Spanish Ministry of Education and Science (predoctoral fellowship to V.F.); the Interdisciplinary Center for Clinical Research, University of Wuerzburg, Germany (A.R. and E.H.); FIS 01/3046 (L.H.); European Grant No. 503351 (European Mantle Cell Lymphoma Network, A.R., E.C., G.O., W.K., and M.D.); the Lymphoma Research Foundation (A.R. and E.C.); Grant No. CICYT SAF 05/5855 from the Spanish Ministry of Science (E.C.); and Grant No. ISCIII-RETIC RD06/0020 from the Spanish Ministry of Health (E.C. and V.M.).

Both E.H. and V.F. contributed equally to this work. E.C. and A.R. are cosenior authors of this study.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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