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dc.contributor.authorLinton, Kim M
dc.contributor.authorHowarth, Christopher
dc.contributor.authorWappett, Mark
dc.contributor.authorNewton, Gillian
dc.contributor.authorLachel, Cynthia
dc.contributor.authorIqbal, J
dc.contributor.authorPepper, Stuart D
dc.contributor.authorByers, Richard J
dc.contributor.authorChan, W J
dc.contributor.authorRadford, John A
dc.date.accessioned2012-11-09T14:24:50Z
dc.date.available2012-11-09T14:24:50Z
dc.date.issued2012-11-09
dc.identifier.citationMicroarray gene expression analysis of fixed archival tissue permits molecular classification and identification of potential therapeutic targets in diffuse large B-cell lymphoma., 14 (3):223-32 J Mol Diagnen_GB
dc.identifier.issn1943-7811
dc.identifier.pmid22446084
dc.identifier.doi10.1016/j.jmoldx.2012.01.008
dc.identifier.urihttp://hdl.handle.net/10541/251601
dc.description.abstractRefractory/relapsed diffuse large B-cell lymphoma (DLBCL) has a poor prognosis. Novel drugs targeting the constitutively activated NF-κB pathway characteristic of ABC-DLBCL are promising, but evaluation depends on accurate activated B cell-like (ABC)/germinal center B cell-like (GCB) molecular classification. This is traditionally performed on gene microarray expression profiles of fresh biopsies, which are not routinely collected, or by immunohistochemistry on formalin-fixed, paraffin-embedded (FFPE) tissue, which lacks reproducibility and classification accuracy. We explored the possibility of using routine archival FFPE tissue for gene microarray applications. We examined Affymetrix HG U133 Plus 2.0 gene expression profiles from paired archival FFPE and fresh-frozen tissues of 40 ABC/GCB-classified DLBCL cases to compare classification accuracy and test the potential for this approach to aid the discovery of therapeutic targets and disease classifiers in DLBCL. Unsupervised hierarchical clustering of unselected present probe sets distinguished ABC/GCB in FFPE with remarkable accuracy, and a Bayesian classifier correctly assigned 32 of 36 cases with >90% probability. Enrichment for NF-κB genes was appropriately seen in ABC-DLBCL FFPE tissues. The top discriminatory genes expressed in FFPE separated cases with high statistical significance and contained novel biology with potential therapeutic insights, warranting further investigation. These results support a growing understanding that archival FFPE tissues can be used in microarray experiments aimed at molecular classification, prognostic biomarker discovery, and molecular exploration of rare diseases.
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of molecular diagnostics : JMDen_GB
dc.subject.meshGene Expression Profiling
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshHumans
dc.subject.meshLymphoma, Large B-Cell, Diffuse
dc.subject.meshMolecular Diagnostic Techniques
dc.subject.meshMolecular Targeted Therapy
dc.subject.meshNF-kappa B
dc.subject.meshOligonucleotide Array Sequence Analysis
dc.subject.meshParaffin Embedding
dc.subject.meshTissue Fixation
dc.titleMicroarray gene expression analysis of fixed archival tissue permits molecular classification and identification of potential therapeutic targets in diffuse large B-cell lymphoma.en
dc.typeArticleen
dc.contributor.departmentThe University of Manchester, Manchester Cancer Research Centre, Manchester, United Kingdom. kim.linton@manchester.ac.uken_GB
dc.identifier.journalJournal of Molecular Diagnosticsen_GB
html.description.abstractRefractory/relapsed diffuse large B-cell lymphoma (DLBCL) has a poor prognosis. Novel drugs targeting the constitutively activated NF-κB pathway characteristic of ABC-DLBCL are promising, but evaluation depends on accurate activated B cell-like (ABC)/germinal center B cell-like (GCB) molecular classification. This is traditionally performed on gene microarray expression profiles of fresh biopsies, which are not routinely collected, or by immunohistochemistry on formalin-fixed, paraffin-embedded (FFPE) tissue, which lacks reproducibility and classification accuracy. We explored the possibility of using routine archival FFPE tissue for gene microarray applications. We examined Affymetrix HG U133 Plus 2.0 gene expression profiles from paired archival FFPE and fresh-frozen tissues of 40 ABC/GCB-classified DLBCL cases to compare classification accuracy and test the potential for this approach to aid the discovery of therapeutic targets and disease classifiers in DLBCL. Unsupervised hierarchical clustering of unselected present probe sets distinguished ABC/GCB in FFPE with remarkable accuracy, and a Bayesian classifier correctly assigned 32 of 36 cases with >90% probability. Enrichment for NF-κB genes was appropriately seen in ABC-DLBCL FFPE tissues. The top discriminatory genes expressed in FFPE separated cases with high statistical significance and contained novel biology with potential therapeutic insights, warranting further investigation. These results support a growing understanding that archival FFPE tissues can be used in microarray experiments aimed at molecular classification, prognostic biomarker discovery, and molecular exploration of rare diseases.


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