scholarly journals Clinical laboratory validation of the MCL35 assay for molecular risk stratification of mantle cell lymphoma

2020 ◽  
Vol 13 (4) ◽  
pp. 231-238
Author(s):  
Colleen A. Ramsower ◽  
Alanna Maguire ◽  
Ryan S. Robetorye ◽  
Andrew L. Feldman ◽  
Sergei I. Syrbu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Stratification ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Clinical Laboratory ◽  
Cell Lymphoma ◽  
Digital Gene Expression ◽  
Digital Gene Expression Profiling ◽  
Mantle Cell

AbstractMantle cell lymphoma (MCL) is a clinically heterogeneous B cell malignancy for which a variety of prognostic factors have been proposed. Previously, a digital gene expression profiling “proliferation signature” capable of risk stratifying MCL was identified and subsequently developed into a multi-analyte prognostic assay, known as the “MCL35” assay. In this study, we sought to explore the performance characteristics of the MCL35 assay in a clinical laboratory and compare results with the Ki67 proliferation marker. The results describe the clinical validation of the MCL35 assay for molecular risk stratification of MCL including accuracy, sensitivity, specificity, use in acid-decalcified bone marrow core biopsies, fixatives, lower limit of RNA input, quality metrics, and other laboratory parameters. The resulting data indicate that this is a robust technique with outstanding reproducibility. Overall, the data support the concept of molecular signatures, as assessed with digital gene expression profiling, for improved standardization and reproducibility for proliferation assessment in MCL.

Biology and Treatment of Mantle Cell Lymphoma in the Genomic Era.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-28-SCI-28
Author(s):  
Adrian Wiestner
Keyword(s):  
Gene Expression ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Genetic Alterations ◽  
Diagnostic Methods ◽  
Genetic Changes ◽  
Mantle Cell

Abstract Abstract SCI-28 The t11;14 translocation, the genetic hallmark of MCL, drives cyclin D1 expression in the tumor cells and historically facilitated the separation of MCL into a distinct entity. FISH cytogenetics are part of the workup and can be particularly helpful to separate leukemic MCL from CLL. Morphology and clinical course of MCL are heterogeneous and might have suggested the presence of different entities. Gene expression profiling answered this concern and provided several important insights: 1. despite the clinical heterogeneity, MCL has a characteristic gene expression profile supporting the accuracy of current diagnostic methods; 2. cyclin D1 negative MCL has the same diagnostic pathologic and gene expression features as cyclin D1 positive MCL, and 3. a gene expression based measure of tumor proliferation is a potent predictor of outcome and identifies patients with survival probabilities ranging from less than 1 year (highly proliferative tumors) to more than 6 years (low proliferation).1 Biologically, the gene expression based proliferation score integrates several acquired genetic changes in the tumor that include deletions of the INK4a/ARF locus encoding the tumor suppressors p14 and p16, amplification of BMI1, and secondary changes in the cyclin D1 locus. Mutations and deletions that alter the structure of the 3'UTR can enhance cyclin D1 mRNA stability,2 and the loss of miR binding sites in this region can enhance protein translation.3 These changes increase cyclin D1 protein resulting in increased proliferation. Additional genetic lesions such as deletions of ATM and p53 affect DNA damage responses pathways. The high frequency of secondary genetic changes in MCL cells may indicate genomic instability and the presence of additional chromosomal aberrations and certain genetic alterations hold prognostic information.4 With the continued refinement of whole genome genetic approaches the goal of identifying crucial pathways and possible driver genes in the pathogenesis of MCL may be within reach. MCL characterized by an antiapoptotic phenotype combined with features of aggressive lymphomas remains an incurable disease and having the worst outcome among all B-cell lymphomas. Biologic markers that predict treatment response and that could give way to targeted therapy have remained elusive. Several new drugs could help overcome treatment resistance and new analytic tools when incorporated into clinical trials may help dissect mechanisms of drug action and resistance. Our approach has been to incorporate gene expression profiling into a clinical trial of bortezomib to directly monitor the effects of the treatment on tumor biology in vivo. We identified an integrated stress response to bortezomib in sensitive tumors that may yield clinically usefully predictors of sensitivity and that could guide the development of improved therapies. 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;3:185-197. 2. Wiestner A, Tehrani M, Chiorazzi M, et al. Point mutations and genomic deletions in Cyclin D1 create stable truncated mRNAs that are associated with increased proliferation rate and shorter survival in mantle cell lymphoma. Blood. 2007. 3. Chen RW, Bemis LT, Amato CM, et al. Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma. Blood. 2008;112:822-829. 4. Salaverria I, Espinet B, Carrio A, et al. Multiple recurrent chromosomal breakpoints in mantle cell lymphoma revealed by a combination of molecular cytogenetic techniques. Genes Chromosomes Cancer. 2008;47:1086-1097. Disclosures Off Label Use: Bortezomib in previously untreated patients with MCL.

Genomic and Gene Expression Profiling Defines Indolent Forms of Mantle Cell Lymphoma

2010 ◽  
Vol 70 (4) ◽  
pp. 1408-1418 ◽  
Author(s):  
V. Fernandez ◽  
O. Salamero ◽  
B. Espinet ◽  
F. Sole ◽  
C. Royo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Mantle Cell

Gene expression profiling of mantle cell lymphoma and its blastoid variant

2001 ◽  
Vol 37 ◽  
pp. S41
Author(s):  
Y. Zhu ◽  
J. Hollmen ◽  
R. Oinonen ◽  
K. Franssila ◽  
Y. Aalto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Mantle Cell

scholarly journals Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways

2005 ◽  
Vol 130 (4) ◽  
pp. 516-526 ◽  
Author(s):  
Edgar Gil Rizzatti ◽  
Roberto Passetto Falcao ◽  
Rodrigo Alexandre Panepucci ◽  
Rodrigo Proto-Siqueira ◽  
Wilma Terezinha Anselmo-Lima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Signalling Pathways ◽  
Lymphoma Cells ◽  
Aberrant Expression ◽  
Expression Of Genes ◽  
Mantle Cell

SOXC and MiR17-92 gene expression profiling defines two subgroups with different clinical outcome in mantle cell lymphoma

2016 ◽  
Vol 55 (6) ◽  
pp. 531-540 ◽  
Author(s):  
Alejandro Roisman ◽  
Fuad Huamán Garaicoa ◽  
Fernanda Metrebian ◽  
Marina Narbaitz ◽  
Dana Kohan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Mantle Cell

scholarly journals Gene Expression Profiling Using Nanostring™ Reveals Differences According to Location, Histology and MIPI Score in Mantle Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5218-5218
Author(s):  
Diana Lucia Martínez Baquero ◽  
Ken H. Young ◽  
Roberto N. Miranda ◽  
L. Jeffrey Medeiros ◽  
Chi Young Ok
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Nodal Involvement ◽  
Lymphoma Cells ◽  
Mantle Cell

Background Mantle cell lymphoma (MCL) is an aggressive B cell neoplasm characterized the by t(11;14)(q13;q32)/CCND1-IGH resulting in overexpression of cyclin D1. Although indolent variants are recognized, MCL is generally aggressive and incurable. The MCL International Prognostic Index (MIPI), gene expression-based proliferation signatures, Ki-67 proliferation index, p53 expression, and aggressive histologic features are used for risk stratification, but the prognostic groups defined by each of these markers are clinically heterogeneous, demonstrating that each parameter alone does not fully account for the clinical behavior of these tumors. In this study, we investigated the gene expression profile of 60 cases of MCL and evaluated which genes had expression patterns that correlate with different clinical and histopathological parameters. Design A total of 60 excisional biopsy specimens of MCL were selected for gene expression profiling. Forty (66%) and 16 (26%) cases were untreated and relapse/persistent samples, respectively; in 4 this unknown was unknown. Biopsy sites included lymph nodes (n=38), spleen (n=10), tonsil (n=6) and various other extranodal tissue sites (n=6). The morphologic features were classic in 27 and aggressive (blastoid/pleomorphic) in 33 patients. MIPI was calculated in selected patients with nodal involvement and whose biopsy was an obtained prior to treatment. Each block contained tumor cells representing ≥ 80% of all cells in the biopsy specimen. RNA was extracted from formalin-fixed paraffin-embedded tissue using the Qiagen Allprep FFPE Kit after deparaffinization, according to the manufacturer's instructions. Gene expression was quantified in 200ng of RNA on the Nanostring™ platform. Normalization for RNA loading was performed using the geometric mean of 40 housekeeping genes with a cutoff value 20. Standard QC and data processing were performed using the nSolver™ Analysis Software. Adjusted p-values were used according to the Benjamini-Hochberg procedure. Results Gene expression profiling was different according to the site of involvement of MCL. Compared with nodal involvement, MCL involving spleen showed overexpression of VEGFA (p <0.01) and NOS (p <0.05). These genes are associated with angiogenesis via the PI3K signaling pathway. Similarly, tonsillar MCL showed overexpression of SFN and HSPB1 (p <0.01) compared with nodal MCL; these genes are related to the MAPK pathway. Different gene expression profiles were observed with respect to histology. Compared to classic variant, blastoid variant demonstrated overexpression of CDK4 (p <0.01) and underexpression of KAT2B and PIK3CG (p <0.01) in all cases. However, no significant differences were found in the gene expression profiles between the classic and pleomorphic variants. We also compared gene expression profiles based on the MIPI score. Compared to cases with a low MIPI score, those with a high MIPI score showed significant overexpression of several genes including SFN, COL11A2, HDAC6 and TP53 (p <0.01). Discussion MCL is a heterogeneous neoplasm, both clinically and genetically. In the present study, significant differences in gene expression profiles were observed based on site of involvement (spleen vs lymph node vs tonsil). However, we cannot exclude the possibility that the result reflects gene expression of non-lymphoma cells in the microenvironment since we did not extract RNA from lymphoma cells. We observed different gene expression profiles in the blastoid variant, but not in the pleomorphic variant compared to the classic variant, suggesting that the biology of pleomorphic variant is probably between the blastoid and the classic variants, possibly closer to the latter. Different gene expression profiles were found with respect to MIPI score, providing scientific support that the MIPI score, in addition to being a useful stratification factor in MCL patients, is reflecting differences in underlying biology of MCL. Disclosures No relevant conflicts of interest to declare.

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