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E-GEOD-66291 - Assessment of MEK-ERK pathway targeting by BRAF, NRAS and KRAS gene mutations in plasma cell dyscrasias [Patient samples]

Status
Released on 1 July 2015, last updated on 19 August 2015
Organism
Homo sapiens
Samples (142)
Array (1)
Protocols (6)
Description
Multiple myeloma (MM) is a malignant disorder characterized by the clonal proliferation of plasma cells (PCs) in the bone marrow (BM). The genetic background and clinical course of the disease are largely heterogeneous, and MM pathophysiology ranges from the premalignant condition of monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM, symptomatic MM, and extramedullary MM/plasma cell leukemia (PCL). Recent genome-wide sequencing efforts have provided the rationale for molecularly aimed treatment approaches, identifying mutations that can be specifically targeted, such as those in the mitogen-activated protein kinase (MAPK) pathway, which represent the most prevalent mutations in MM. Among these, mutations affecting BRAF gene, detected in 4-15% of patients, are of potential immediate clinical relevance due to the availability of effective inhibitors of this serine-threonine kinase which are in fact being explored also in myeloma. In this study, we screened by next generation sequencing (NGS) a large and representative series of intramedullary and extramedullary MM patients, including primary and secondary plasma cell leukemia (pPCL and sPCL, respectively), for mutations in BRAF, NRAS and KRAS genes. We evaluated the relationship of identified variants with other clinical and biological features and determined the transcriptional signature associated with MAPK pathway activation in MM. To identify transcriptomic profiles possibly related to BRAF, NRAS and KRAS mutations found in our study, we investigated by Affymetrix microarray technology a large fraction (n=142) of the samples analyzed by NGS, including wild-type patients for all the three genes and cases carrying mutations in at least one of them. Assuming that alterations present in a very limited number of malignant PCs might not appreciably affect gene expression, we chose to arbitrarily establish 20% as the lower variant allele frequency cut-off to perform supervised analyses.
Experiment type
transcription profiling by array 
Contacts
Agostino Cortelezzi, Antonino Neri, Antonio Palumbo, Giovanni Tonon, Giulia Milesi, Katia Todoerti, Luca Agnelli, Luca Baldini, Mara Mazzoni, Maria A Greco, Marta Lionetti, Martina Manzoni, Marzia Barbieri, Pellegrino Musto, Serena Galletti, Simona Marzorati, Sonia Fabris
Citation
Molecular spectrum of BRAF, NRAS and KRAS gene mutations in plasma cell dyscrasias: implication for MEK-ERK pathway activation. Lionetti M, Barbieri M, Todoerti K, Agnelli L, Marzorati S, Fabris S, Ciceri G, Galletti S, Milesi G, Manzoni M, Mazzoni M, Greco A, Tonon G, Musto P, Baldini L, Neri A.
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