Transcriptomics

Dataset Information

3

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


ABSTRACT: 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.

ORGANISM(S): Homo sapiens  

SUBMITTER: Luca Agnelli   Simona Marzorati  Giulia Milesi  Katia Todoerti  Giovanni Tonon  Luca Baldini  Martina Manzoni  Maria A Greco  Mara Mazzoni  Marzia Barbieri  Agostino Cortelezzi  Serena Galletti  Antonio Palumbo  Pellegrino Musto  Marta Lionetti  Antonino Neri  Sonia Fabris 

PROVIDER: E-GEOD-66291 | ArrayExpress | 2015-07-01

SECONDARY ACCESSION(S): GSE66291PRJNA276449

REPOSITORIES: GEO, ArrayExpress

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Publications


Multiple myeloma (MM) is a clinically and genetically heterogeneous plasma cell (PC) malignancy. Whole-exome sequencing has identified therapeutically targetable mutations such as those in the mitogen-activated protein kinase (MAPK) pathway, which are the most prevalent MM mutations. We used deep sequencing to screen 167 representative patients with PC dyscrasias [132 with MM, 24 with primary PC leukemia (pPCL) and 11 with secondary PC leukemia (sPCL)] for mutations in BRAF, NRAS and KRAS, which  ...[more]

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