A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: results from the Fondazione Italiana Linfomi MCL-0208 trial

Riccardo Bomben, Simone Ferrero, Tiziana D'Agaro, Michele Dal Bo, Alessandro Re, Andrea Evangelista, Angelo Michele Carella, Alberto Zamò, Umberto Vitolo, Paola Omedè, Chiara Rusconi, Luca Arcaini, Luigi Rigacci, Stefano Luminari, Andrea Piccin, Delong Liu, Adrian Wiestner, Gianluca Gaidano, Sergio Cortelazzo, Marco Ladetto, Valter Gattei, Riccardo Bomben, Simone Ferrero, Tiziana D'Agaro, Michele Dal Bo, Alessandro Re, Andrea Evangelista, Angelo Michele Carella, Alberto Zamò, Umberto Vitolo, Paola Omedè, Chiara Rusconi, Luca Arcaini, Luigi Rigacci, Stefano Luminari, Andrea Piccin, Delong Liu, Adrian Wiestner, Gianluca Gaidano, Sergio Cortelazzo, Marco Ladetto, Valter Gattei

Abstract

Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptorlow and B-cell receptorhigh) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK), was used to classify the 83 cases (43 B-cell receptorlow and 40 B-cell receptorhigh). The B-cell receptorhigh signature associated with shorter progression-free survival (P=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (P=0.0014 and P=0.029, respectively) in combination with high (>30%) Ki-67 staining, and was an independent predictor of short progression- free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6- gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homogenously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL- 0208 clinical trial. (clinicaltrials.gov identifier: 02354313).

Trial registration: ClinicalTrials.gov NCT02354313.

Copyright © 2018 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Gene Expression Profile (GEP) analysis of 27 mantle cell lymphoma samples. (A) Principal Component Analysis (PCA) scores represented in a 3D scatter plot. One point per array/sample is shown. Black line indicates separation between PCA classes. (B) Hierarchical clustering of 14 group-1 cases and 13 group-2 cases, using 50,739 probes. (C) Hierarchical clustering of 14 group1 cases and 13 group2 cases, using the 922 differentially expressed probes. Color codes for gene expression values refer to mean centered log-ratio values.
Figure 2.
Figure 2.
6-gene signature and Decision Tree (DT) prediction model. (A) Gene Expression Profile data of BCRlow and BCRhigh MCL samples were tested using Gene set enrichment analysis (GSEA). Reported are the significant gene sets differentially expressed and related to the B-Cell Receptor (BCR) pathway. (B) Venn diagram derived by merging the differentially expressed probes and the genes belonging to the BCR related gene sets. In bold genes selected as the 6-gene signature. (C) Hierarchical clustering of 14 BCRlow cases and 13 BCRhigh cases, using the six gene values. Color codes for gene expression values refer to mean centered log-ratio values. (D) Hierarchical clustering of 8 BCRlow cases and 9 BCRhigh cases belonging to the training set of DT prediction model, using the six gene qRT-PCR values. (E) Hierarchical clustering of 6 BCRlow cases and 4 BCRhigh cases belonging to the validation set of DT prediction model, using the six gene qRT-PCR values. Bar under the heat-map refers to prediction generated by the DT prediction model. Color codes for gene expression values refer to mean centered log-ratio values.
Figure 3.
Figure 3.
BCRhigh mantle cell lymphoma (MCL) group is associated with a worse clinical outcome. Kaplan-Meier curves obtained by comparing progression-free survival intervals of 23 BCRlow MCL cases with 23 BCRhigh MCL cases. The number of patients in each group is reported under relative categories; P refers to log- rank test.
Figure 4.
Figure 4.
BCRhigh mantle cell lymphoma (MCL) group is associated with a worse clinical outcome (overall series). (A) Kaplan-Meier curves obtained by comparing progression-free survival (PFS) intervals of 43 BCRlow MCL cases with 40 BCRhigh MCL cases. (B) Kaplan-Meier curves obtained by comparing PFS intervals of 19 BCRlow and low Ki-67 MCL cases, with 20 BCRlow and high Ki-67 MCL cases, with 21 BCRhigh and Ki-67 low MCL cases, with 10 BCRhigh and Ki-67 high MCL cases. (C) Kaplan-Meier curves obtained by comparing overall survival (OS) intervals of 43 BCRlow MCL cases with 40 BCRhigh MCL cases. (D) Kaplan-Meier curves obtained by comparing OS intervals of 19 BCRlow and low Ki-67 MCL cases, with 20 BCRlow and high Ki-67 MCL cases, with 21 BCRhigh and Ki- 67 low MCL cases, with 10 BCRhigh and Ki-67 high MCL cases. The number of patients in each group is reported under relative categories; P refers to log-rank test.

References

    1. Dreyling M, Ferrero S, Hermine O. How to manage mantle cell lymphoma. Leukemia. 2014;28(11):2117–2130.
    1. Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol. 2016; 34(11):1256–1269.
    1. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019–5032.
    1. Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest. 2012;122(10):3416–3423.
    1. Dreyling M, Ferrero S, Vogt N, Klapper W. New paradigms in mantle cell lymphoma: is it time to risk-stratify treatment based on the proliferative signature? Clin Cancer Res. 2014;20(20):5194–5206.
    1. Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood. 2009;114(8):1469–1476.
    1. Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27(4):511–518.
    1. Zucca E, Roggero E, Pinotti G, et al. Patterns of survival in mantle cell lymphoma. Ann Oncol. 1995;6(3):257–262.
    1. Barista I, Romaguera JE, Cabanillas F. Mantle-cell lymphoma. Lancet Oncol. 2001;2(3):141–148.
    1. Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009; 27(8):1209–1213.
    1. Dreyling M, Ferrero S. The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive? Haematologica. 2016;101(2):104–114.
    1. Geisler CH, Kolstad A, Laurell A, et al. The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT). Blood. 2010;115(8):1530–1533.
    1. Hoster E, Rosenwald A, Berger F, et al. Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016; 34(12):1386–1396.
    1. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558–565.
    1. Bea S, Valdes-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA. 2013;110(45):18250–18255.
    1. Zhang J, Jima D, Moffitt AB, et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014;123(19):2988–2996.
    1. Katzenberger T, Petzoldt C, Holler S, et al. The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood. 2006;107(8):3407.
    1. Hartmann E, Fernandez V, Moreno V, et al. Five-gene model to predict survival in mantle-cell lymphoma using frozen or formalin- fixed, paraffin-embedded tissue. J Clin Oncol. 2008;26(30):4966–4972.
    1. Ek S, Bjorck E, Porwit-MacDonald A, Nordenskjold M, Borrebaeck CA. Increased expression of Ki-67 in mantle cell lymphoma is associated with de-regulation of several cell cycle regulatory components, as identified by global gene expression analysis. Haematologica. 2004;89(6):686–695.
    1. Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3(2):185–197.
    1. Mozos A, Royo C, Hartmann E, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica. 2009;94(11):1555–1562.
    1. Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res. 2012;72(20):5307–5316.
    1. Majlis A, Pugh WC, Rodriguez MA, Benedict WF, Cabanillas F. Mantle cell lymphoma: correlation of clinical outcome and biologic features with three histologic variants. J Clin Oncol. 1997;15(4):1664–1671.
    1. Wiestner A, Tehrani M, Chiorazzi M, et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood. 2007;109(11):4599–4606.
    1. Jares P, Colomer D, Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer. 2007;7(10):750–762.
    1. Determann O, Hoster E, Ott G, et al. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti- CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008; 111(4):2385–2387.
    1. Perez-Galan P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011;117(1):26–38.
    1. Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov. 2013; 12(3):229–243.
    1. Akhter A, Street L, Ghosh S, et al. Concomitant high expression of Toll-like receptor (TLR) and B-cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma. Hematol Oncol. 2015;35(1):79–86.
    1. Saba NS, Liu D, Herman SE, et al. Pathogenic role of B-cell receptor signaling and canonical NF-kappaB activation in mantle cell lymphoma. Blood. 2016; 128(1):82–92.
    1. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507–516.
    1. Cortellazzo S, Martelli M, Ladetto M, Ferrero S, Ciccone G, Evangelista A, et al. High dose sequential chemotherapy with rituximab and ASCT as first line therapy in adult MCL patients: clinical and molecular response of the MCL-0208 trial, a FIL study. Haematologica. 2015;100(s1):3.
    1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Blood. 2016; 127(20):2375–2390.
    1. Bomben R, Gobessi S, Dal BM, et al. The miR-17-92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes. Leukemia. 2012;26(7):1584–1593.
    1. Dal Bo M, D’Agaro T, Gobessi S, et al. The SIRT1/TP53 axis is activated upon B-cell receptor triggering via miR-132 up-regulation in chronic lymphocytic leukemia cells. Oncotarget. 2015;6(22):19102–19117.
    1. Draghici S, Khatri P, Martins RP, Ostermeier GC, Krawetz SA. Global functional profiling of gene expression. Genomics. 2003;81(2):98–104.
    1. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545–15550.
    1. Scott DW, Abrisqueta P, Wright GW, et al. New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin- Embedded Biopsies. J Clin Oncol. 2017; 35(15):1668–1677.
    1. Nera KP, Kohonen P, Narvi E, et al. Loss of Pax5 promotes plasma cell differentiation. Immunity. 2006;24(3):283–293.
    1. Hadzidimitriou A, Agathangelidis A, Darzentas N, et al. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood. 2011;118(11):3088–3095.
    1. Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol. 2013; 13(8):578–591.
    1. Wang ML, Blum KA, Martin P, et al. Long- term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015; 126(6):739–745.
    1. Rahal R, Frick M, Romero R, et al. Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat Med. 2014;20(1):87–92.
    1. Lenz G, Balasubramanian S, Goldberg J, Rizo A, Schaffer M, Phelps C, et al. Sequence variants in patients with primary and acquired resistance to ibrutinib in the phase 3 MCL3001 (RAY) trial. Haematologica. 2016;101(s1):155.

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