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Prognostic analysis of mantle cell lymphoma genomes

ABSTRACT: Mantle cell lymphoma is characterized by a t(11;14) chromosomal translocation; however, it alone is insufficient to result in the disease. A number of secondary genetic alterations have been proposed as essential in MCL pathogenesis. Amongst these, numerous copy number altered regions remain ill-defined, both for location and prognostic significance. In this study we examined in detail the genomes of a panel of 52 MCL cases. Relating gene dosage alterations to disease outcome, we found seven loci that correlated with overall survival. A survival model was constructed based on four of these loci (P = 5.87 x 10-6). Using serial analysis of gene expression and quantitative PCR we investigated the expression of genes within these altered regions and determined that CCNI and CCNG2 may be important in MCL pathogenesis (P = 0.0201 and P = 0.0292, respectively). Our findings reinforce the hypothesis that cell cycle deregulation and apoptosis are key factors in MCL pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE13331 | GEO | 2009/12/01

SECONDARY ACCESSION(S): PRJNA109847

REPOSITORIES: GEO

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Prognostic analysis of mantle cell lymphoma genomes

Project description:Mantle cell lymphoma is characterized by a t(11;14) chromosomal translocation; however, it alone is insufficient to result in the disease. A number of secondary genetic alterations have been proposed as essential in MCL pathogenesis. Amongst these, numerous copy number altered regions remain ill-defined, both for location and prognostic significance. In this study we examined in detail the genomes of a panel of 52 MCL cases. Relating gene dosage alterations to disease outcome, we found seven loci that correlated with overall survival. A survival model was constructed based on four of these loci (P = 5.87 x 10-6). Using serial analysis of gene expression and quantitative PCR we investigated the expression of genes within these altered regions and determined that CCNI and CCNG2 may be important in MCL pathogenesis (P = 0.0201 and P = 0.0292, respectively). Our findings reinforce the hypothesis that cell cycle deregulation and apoptosis are key factors in MCL pathogenesis. Array CGH, Long-SAGE, and qPCR were utilized to determine regions of the genome that have prognostic significance when altered in copy number in MCL.

2010-10-01 | E-GEOD-13331 | biostudies-arrayexpress

Integrated genomic profiling in mantle cell lymphoma

Project description: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 likely account for the varying 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 (GEDI) 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 (CNN-LOH) 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 two 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, since decreased expression of its members MOBKL2A, MOBKL2B and LATS2 was associated with inferior outcome also in an independent validation series of 32 MCL. Sixty-four primary MCL specimens from previously untreated patients were investigated with Affymetrix HG U133 plus 2.0 gene expression arrays.

2011-03-31 | E-GEOD-21452 | biostudies-arrayexpress

Integrated genomic profiling in mantle cell lymphoma

2011-04-01 | GSE21452 | GEO

The Gene Expression Study (GEP) was based on a 6 MCL cell line models.

Project description:The aggressive clinical behavior of mantle cell lymphoma (MCL) is attributed to specific genetic and molecular mechanisms involved in its pathogenesis, mainly the t(11;14)(q13;q32) traslocation and cyclin D1 (CCND1) overexpression. Nevertheless, evidence of a certain degree of heterogeneity has been disclosed by gene expression profile (GEP) and (immuno)genetic/immunohistochemistry studies. AIM: To use a GEP approach in MCL cell line models.

2017-12-31 | GSE89615 | GEO

The Gene Expression Study (GEP) was based on a cohort of 27 MCL cases enrolled in the Fondazione Italiana Linfomi (FIL)-MCL-0208 randomized Italian clinical trial.

Project description:The aggressive clinical behavior of mantle cell lymphoma (MCL) is attributed to specific genetic and molecular mechanisms involved in its pathogenesis, mainly the t(11;14)(q13;q32) traslocation and cyclin D1 (CCND1) overexpression. Nevertheless, evidence of a certain degree of clinical/biological heterogeneity has been disclosed by gene expression profile (GEP) and (immuno)genetic/immunohistochemistry studies. AIM: To use a GEP approach to identify MCL subsets with peculiar clinical/biological features in the context of of MCL patients treated homogeneously with an autologous transplantation-based program.

2017-12-31 | GSE89447 | GEO

Gene expression of mantle cell lymphoma-initiating cells from primary tumor samples

2014-08-02 | GSE60023 | GEO

RNA-sequencing in MCL cell lines after silencing cyclin D1

Project description:Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell cycle regulator and also has a role in transcription, but the effect of the latter in tumorigenesis remains largely unknown. Here, we investigated the transcriptional role of cyclin D1 in MCL and its impact on the pathogenesis of this neoplasm. Integrating genome-wide expression analysis of cyclin D1-silenced and overexpressing cells with cyclin D1 chromatin binding profiles, we identified a cyclin D1-activated transcriptional program in MCL cells.

2021-06-30 | GSE144106 | GEO

Gene expression of mantle cell lymphoma-initiating cells from primary tumor samples

Project description:In this study we compared the expression of 30215 genes in mantle cell lymphoma-initiating cells (MCL-ICs) with mantle cell lymphoma-non-initiating cells (MCL-non-ICs) and B-cells from healthy donor Three samples each of MCL-ICs and MCL-non-ICs were isolated from aphresis of 3 mantle cell lymphoma primary patient samples and 2 samples of CD19+ Bcells isolated from buffy coats of healthy donor Microarray include both coding and non-coding transcripts but only mRNA coding transcript were included in this study.

2014-08-02 | E-GEOD-60023 | biostudies-arrayexpress

CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma [Agilent]

Project description:Cyclin D1-negative mantle cell lymphomas (MCL) are not well characterized, in part due to the difficulties in their recognition. SOX11 has been recently identified as a reliable biomarker of MCL, also expressed in the cyclin D1-negative variant. We investigated 40 lymphomas with MCL morphology and immunophenotype, negative for cyclin D1 expression/t(11;14)(q13;q32) but SOX11-positive. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and had a poor outcome (5-year overall survival 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18/22 cases, in particular with light chains (10 IGK@, 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2 and CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1-negative SOX11-positive MCL analyzed by copy number arrays were similar to the conventional cyclin D1/SOX11-positive MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome to the patients. This comprehensive characterization of a large series of cyclin D1-negative MCL indicates that these tumors are clinically and biologically similar to the conventional cyclin D1-positive MCL and provides a basis for the proper identification and clinical management of these patients. Copy number analysis of Agilent 1*1M arrays was performed for 27 MCL, with sex-matched control DNAs and without duplicates or dye-swapt.

2012-12-19 | E-GEOD-42917 | biostudies-arrayexpress

CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma [Affymetrix]

Project description:Cyclin D1-negative mantle cell lymphomas (MCL) are not well characterized, in part due to the difficulties in their recognition. SOX11 has been recently identified as a reliable biomarker of MCL, also expressed in the cyclin D1-negative variant. We investigated 40 lymphomas with MCL morphology and immunophenotype, negative for cyclin D1 expression/t(11;14)(q13;q32) but SOX11-positive. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and had a poor outcome (5-year overall survival 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18/22 cases, in particular with light chains (10 IGK@, 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2 and CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1-negative SOX11-positive MCL analyzed by copy number arrays were similar to the conventional cyclin D1/SOX11-positive MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome to the patients. This comprehensive characterization of a large series of cyclin D1-negative MCL indicates that these tumors are clinically and biologically similar to the conventional cyclin D1-positive MCL and provides a basis for the proper identification and clinical management of these patients. This Series contains copy number analysis of 500K Affymetrix SNP arrays for five MCL (5 hybridizations of wih Nsp 250K array and 5 hybridizations with Sty 250K arrays, that combined are the 500K array).

2012-12-19 | E-GEOD-42935 | biostudies-arrayexpress

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