Molecular spectrum of <i>BRAF, NRAS</i> and <i>KRAS</i> gene mutations in plasma cell dyscrasias: implication for MEK-ERK pathway activation

Abstract

// Marta Lionetti 1 , Marzia Barbieri 2 , Katia Todoerti 3 , Luca Agnelli 1 , Simona Marzorati 1 , Sonia Fabris 2 , Gabriella Ciceri 1 , Serena Galletti 1 , Giulia Milesi 2 , Martina Manzoni 1 , Mara Mazzoni 4 , Angela Greco 4 , Giovanni Tonon 5 , Pellegrino Musto 3 , Luca Baldini 1,2 and Antonino Neri 1,2 1 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy 2 Hematology Unit, Fondazione IRCCS Ca&rsquo; Granda, Ospedale Maggiore Policlinico, Milan, Italy 3 Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy 4 Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 5 Functional Genomics of Cancer Unit, Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy Correspondence to: Antonino Neri, email: // Marta Lionetti, email: // Keywords : multiple myeloma, plasma cell leukemia, RAS, BRAF, next generation sequencing Received : April 17, 2015 Accepted : May 31, 2015 Published : June 10, 2015 Abstract 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 were respectively found in 12%, 23.9% and 29.3% of cases. Overall, the MAPK pathway was affected in 57.5% of the patients (63.6% of those with sPCL, 59.8% of those with MM, and 41.7% of those with pPCL). The majority of BRAF variants were comparably expressed at transcript level. Additionally, gene expression profiling indicated the MAPK pathway is activated in mutated patients. Finally, we found that vemurafenib inhibition of BRAF activation in mutated U266 cells affected the expression of genes known to be associated with MM. Our data confirm and extend previous published evidence that MAPK pathway activation is recurrent in myeloma; the finding that it is mediated by BRAF mutations in a significant fraction of patients has potentially immediate clinical implications.