Rearrangement of<i>MYC</i>Is Associated With Poor Prognosis in Patients With Diffuse Large B-Cell Lymphoma Treated in the Era of Rituximab

Barrans, Sharon; Crouch, Simon; Smith, Alex; Turner, Kathryn; Owen, Roger G.; Patmore, Russell; Roman, Eve; Jack, Andrew

doi:10.1200/jco.2009.26.3947

Cited by 521 publications

(468 citation statements)

References 38 publications

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“…The presence of MYC rearrangements in patients with diffuse large B-cell lymphoma treated with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) has been shown to be associated with poor prognosis. 3,4 In particular, the so-called 'double-hit' lymphomas that are characterized by MYC rearrangement and a concurrent rearrangement of other B-cell lymphomaassociated genes such as BCL2 or BCL6 are associated with poor response to therapy, aggressive clinical course and dismal prognosis. [5][6][7] These lymphomas are classified as 'B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma' in the current 2008 WHO classification of hematopoietic neoplasms.…”

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confidence: 99%

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

et al. 2015

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Recent studies have shown that immunohistochemical evaluation of MYC protein expression in diffuse large B-cell lymphoma is a useful prognostic tool with high concordance rate among pathologists. Concordance in these studies was assessed among few pathologists from one institution by scoring tissue microarrays. In daily practice, MYC evaluation is performed on entire tumor sections by a diverse group of pathologists. In our study, nine hematopathologists from two institutions scored whole-tissue sections of two sets of cases. The training set included 13 cases of diffuse large B-cell lymphoma and 4 cases of Burkitt lymphoma. The validation set included 18 cases of diffuse large B-cell lymphoma and 1 case of Burkitt lymphoma. MYC positivity was defined as Z40% of tumor cells demonstrating nuclear staining similar to prior studies. The mean score for each case was used to determine MYC status with discrepant cases defined as having any score causing a different MYC status designation. Discrepant cases from the training set were characterized by staining heterogeneity, extensive necrosis or crush artifact and had mean scores within 15 percentage points of 40%. Cases from the validation set that demonstrated any of these features were scored twice on two different days. Overall concordance was moderate (Kappa score: 0.68, P-valueo0.001) with no significant change between the two sets (Kappa scores: 0.69 vs 0.67). Thirty-nine percent of cases were discrepant. The findings indicate that a significant number of diffuse large B-cell lymphomas are inherently difficult to score due to staining heterogeneity. The effect of heterogeneity can be under-represented when concordance is measured among few pathologists scoring tissue microarrays. Careful scoring strategy in our study failed to improve concordance. In the absence of specific instructions on how to deal with heterogeneity, caution is advised when evaluating MYC expression in diffuse large B-cell lymphoma.

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confidence: 99%

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

et al. 2015

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“…13,16 In each case, mRNA sample from FFPE lymphoma tissue was available from the previous study. Local ethical guidelines were followed for the use of archival tissues for research with the approval of the ethics committees of the involved institutions.…”

Section: Materials and Methods Patient Materials And Data Setsmentioning

confidence: 99%

“…13,16 Primer Design and Validation PCR primer pairs were designed for the 20 classifier genes that are commonly present in different microarray platforms, 5 NF-kB target genes that are characteristically enriched in their expression in ABC-DLBCL, 4,5 and 3 reference genes (Supplementary Table S1). The reference genes were selected as they are stably expressed in lymphoid tissues, but not affected by genomic copy number changes in lymphoma, nor involved in lymphomagenesis.…”

Section: Materials and Methods Patient Materials And Data Setsmentioning

confidence: 99%

“…The performance of these basic classifiers was ranked according to F-measure and ROC area value as described previously. 13 The resulting top basic machine-learning classifiers were systematically combined, trained, and crossvalidated on the Wright data set, and the resulting best classifier was then tested on the Affymetrix GSE10846 data set from FF tissues, 17 the Illumina WG-DASL GSE32918 data set from FFPE tissues, 13,16 and the Affymetrix data set from FF tissues by Monti et al (http://www.ncbi.nlm.nih.gov/gds/). 18 Finally, the validated best classifier was applied to the qRT-PCR data generated on the FFPE tissues in the present study.…”

Section: Dlbcl Classifier Testing and Rankingmentioning

confidence: 99%

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Diffuse large B-cell lymphoma: sub-classification by massive parallel quantitative RT-PCR

Xue

Zeng

Gao

et al. 2015

Laboratory Investigation

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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity with remarkably variable clinical outcome. Gene expression profiling (GEP) classifies DLBCL into activated B-cell like (ABC), germinal center B-cell like (GCB), and Type-III subtypes, with ABC-DLBCL characterized by a poor prognosis and constitutive NF-kB activation. A major challenge for the application of this cell of origin (COO) classification in routine clinical practice is to establish a robust clinical assay amenable to routine formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies. In this study, we investigated the possibility of COO-classification using FFPE tissue RNA samples by massive parallel quantitative reverse transcription PCR (qRT-PCR). We established a protocol for parallel qRT-PCR using FFPE RNA samples with the Fluidigm BioMark HD system, and quantified the expression of the COO classifier genes and the NF-kB targeted-genes that characterize ABC-DLBCL in 143 cases of DLBCL. We also trained and validated a series of basic machine-learning classifiers and their derived meta classifiers, and identified SimpleLogistic as the top classifier that gave excellent performance across various GEP data sets derived from fresh-frozen or FFPE tissues by different microarray platforms. Finally, we applied SimpleLogistic to our data set generated by qRT-PCR, and the ABC and GCB-DLBCL assigned showed the respective characteristics in their clinical outcome and NF-kB target gene expression. The methodology established in this study provides a robust approach for DLBCL sub-classification using routine FFPE diagnostic biopsies in a routine clinical setting. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity with remarkably variable clinical outcome. Among the many biomarkers investigated so far, only the molecular subtypes by cell of origin (COO) classification, the MYC involved chromosome translocation and TP53 mutation, have been consistently shown to bear prognostic value in the setting of rituximab-containing chemotherapy regimens. The COO-classification by whole-genome expression profiling (GEP) classifies DLBCL into activated B-cell like (ABC), germinal center B-cell like (GCB), and Type-III (unclassified) subtypes, with the ABC-DLBCL characterized by a poor prognosis and constitutive NF-kB activation. 1-5 The original classification was based on similarity of DLBCL gene expression to the activated peripheral blood B cells or normal germinal center B cells by hierarchical clustering analysis. 1 Subsequently, Wright et al 3 identified 27 genes that were most discriminative in their expression between ABC and GCB-DLBCL, and developed a linear predictor score (LPS) algorithm for COO-classification. These seminal works are entirely based on retrospective investigations of fresh-frozen (FF) lymphoma tissues. A major challenge for the application of this COO-classification in clinical practice is to establish a robust clinical assay amenable to routine formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies.Several immunohist...

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“…9,10 Several studies have reported that MYC translocations independently predicted significantly poor survival in DLBCL patients. [11][12][13][14][15][16] However, other studies found inconsistent results [17][18][19] or limitations of its prognostic significance. 20,21 The clinical significance of Myc overexpression in DLBCL has also been the source of much attention and controversy.…”

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confidence: 99%

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

et al. 2015

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MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n = 344) and Myc expression (n = 535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall

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Rearrangement ofMYCIs Associated With Poor Prognosis in Patients With Diffuse Large B-Cell Lymphoma Treated in the Era of Rituximab

Cited by 521 publications

References 38 publications

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

Diffuse large B-cell lymphoma: sub-classification by massive parallel quantitative RT-PCR

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

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