Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling

Institute of Pathology, University of Wuerzburg, Josef-Schneider-Strasse 2, Wuerzburg, Germany.
Blood (Impact Factor: 10.45). 08/2010; 116(6):953-61. DOI: 10.1182/blood-2010-01-263806
Source: PubMed


The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2A locus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2 was associated with inferior outcome, including an independent validation series of 32 MCLs.

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Available from: Wing C Chan, Aug 24, 2015
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    • "Indeed, additional genetic events are frequent in MCL and interfere with cell cycle regulation, cellular response to DNA damage, apoptosis , and survival pathway (Jares et al., 2007; Dreyling et al., 2011; Cortelazzo et al., 2012). These genetic abnormalities have been studied by sophisticated molecular cytogenetic techniques, such as comparative genomic hybridization arrays (CGH-CGHarray) (Jarosov a et al., 2004; Rubio- Moscardo et al., 2005; Salaverria et al., 2007; Campo et al., 2011), gene expression profiling (Fernandez et al., 2010), single-nucleotide polymorphism arrays (Be a et al., 2009; Hartmann et al., 2010), quantitative polymerase chain reaction (Kienle et al., 2007; Jardin et al., 2009), and transcriptome sequencing (Kridel et al., 2012). However , these techniques are not routinely performed and therefore do not influence the treatment decision . "
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    ABSTRACT: Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an "indolent" evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra-hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of "indolent" patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2014 · Genes Chromosomes and Cancer
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    • "TNFRSF10A and TNFRSF10B have been shown to be inactivated in DLBCL and in mantle cell lymphoma (MCL) (Rubio- Moscardo et al, 2005; Hartmann et al, 2008). MCPH1, involved in DNA damage repair, has been very recently reported down-regulated in MCL with del(8p) (Hartmann et al, 2010). Our study presented some limitations. "
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    ABSTRACT: The integration of molecular and clinical information to tailor treatments remains an important research challenge in chronic lymphocytic leukaemia (CLL). This study aimed to identify genomic lesions associated with a poor outcome and a higher risk of histological transformation. A mono-institutional cohort of 147 cases was used as the test series, and a multi-institutional cohort of 176 cases as a validation series. Genomic profiles were obtained using Affymetrix SNP 6.0. The impact of the recurrent minimal common regions (MCRs) on overall survival was evaluated by univariate analysis followed by multiple-test correction. The independent prognostic significance was assessed by multivariate analysis. Eight MCRs showed a prognostic impact: gains at 2p25.3-p22.3 (MYCN), 2p22.3, 2p16.2-p14 (REL), 8q23.3-q24.3 (MYC), losses at 8p23.1-p21.2, 8p21.2, and of the TP53 locus. Gains at 2p and 8q and TP53 inactivation maintained prognostic significance in multivariate analysis and a hierarchical model confirmed their relevance. Gains at 2p also determined a higher risk of Richter syndrome transformation. The prediction of outcome for CLL patients might be improved by evaluating the presence of gains at 2p and 8q as novel genomic regions besides those included in the 'standard' fluorescence in situ hybridization panel.
    Full-text · Article · Sep 2011 · British Journal of Haematology
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    • "Chromosomal changes, like translocations or gene amplifications, constitute one of the main mechanisms leading to deregulated gene expression in lymphomas [15]. In the case of SOX11, chromosomal changes affecting band 2p25.2 (where SOX11 is located) have not been identified in MCL, BL or ALL [16], [17], [18], [19], [20]. Therefore, other, non-genetic mechanisms should be responsible for its expression pattern in these lymphoid neoplasms. "
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    ABSTRACT: Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.
    Full-text · Article · Jun 2011 · PLoS ONE
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