title: Whole-exome sequencing of primary plasma cell leukemia discloses heterogeneous mutational patterns.
abstract: Primary plasma cell leukemia (pPCL) is a rare and aggressive form of plasma cell dyscrasia and may represent a valid model for high-risk multiple myeloma (MM). To provide novel information concerning the mutational profile of this disease, we performed the whole-exome sequencing of a prospective series of 12 pPCL cases included in a Phase II multicenter clinical trial and previously characterized at clinical and molecular levels. We identified 1, 928 coding somatic non-silent variants on 1, 643 genes, with a mean of 166 variants per sample, and only few variants and genes recurrent in two or more samples. An excess of C > T transitions and the presence of two main mutational signatures (related to APOBEC over-activity and aging) occurring in different translocation groups were observed. We identified 14 candidate cancer driver genes, mainly involved in cell-matrix adhesion, cell cycle, genome stability, RNA metabolism and protein folding. Furthermore, integration of mutation data with copy number alteration profiles evidenced biallelically disrupted genes with potential tumor suppressor functions. Globally, cadherin/Wnt signaling, extracellular matrix and cell cycle checkpoint resulted the most affected functional pathways. Sequencing results were finally combined with gene expression data to better elucidate the biological relevance of mutated genes. This study represents the first whole-exome sequencing screen of pPCL and evidenced a remarkable genetic heterogeneity of mutational patterns. This may provide a contribution to the comprehension of the pathogenetic mechanisms associated with this aggressive form of PC dyscrasia and potentially with high-risk MM.
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cifola
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.|Hematology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Lionetti
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Pinatel
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Todoerti
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mangano
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pietrelli
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.|Hematology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fabris
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.|Hematology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mosca
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Simeon
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, La Sapienza University, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.affiliation: Hematology Unit, Azienda Ospedaliera di Cosenza, Cosenza, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Morabito
authors.affiliation: Hematologic Clinic, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Offidani
authors.affiliation: Department of Biomedical Sciences, Division of Hematology, Ospedale Ferrarotto, University of Catania, Catania, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.affiliation: Hematology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Department of Hematology, Ospedale S. Eugenio, Tor Vergata University, Rome, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Caravita
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Battaglia
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: De Bellis
authors.affiliation: Division of Hematology, University of Torino, A.O.U. San Giovanni Battista, Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.affiliation: Scientific Direction, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy.
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Musto
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.|Hematology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
mesh_terms: D016000:Cluster Analysis; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome; D006801:Humans; D007952:Leukemia, Plasma Cell / Q000235:genetics*
keywords: multiple myeloma; mutations; plasma cell leukemia; whole-exome sequencing