Research Papers:

Whole-exome sequencing of primary plasma cell leukemia discloses heterogeneous mutational patterns

Ingrid Cifola, Marta Lionetti, Eva Pinatel, Katia Todoerti, Eleonora Mangano, Alessandro Pietrelli, Sonia Fabris, Laura Mosca, Vittorio Simeon, Maria Teresa Petrucci, Fortunato Morabito, Massimo Offidani, Francesco Di Raimondo, Antonietta Falcone, Tommaso Caravita, Cristina Battaglia, Gianluca De Bellis, Antonio Palumbo, Pellegrino Musto and Antonino Neri _

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Oncotarget. 2015; 6:17543-17558. https://doi.org/10.18632/oncotarget.4028

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Ingrid Cifola1,*, Marta Lionetti2,3,*, Eva Pinatel1, Katia Todoerti4, Eleonora Mangano1, Alessandro Pietrelli1, Sonia Fabris2,3, Laura Mosca2,3, Vittorio Simeon4, Maria Teresa Petrucci5, Fortunato Morabito6, Massimo Offidani7, Francesco Di Raimondo8, Antonietta Falcone9, Tommaso Caravita10, Cristina Battaglia1,11, Gianluca De Bellis1, Antonio Palumbo12, Pellegrino Musto13, Antonino Neri2,3

1Institute for Biomedical Technologies, National Research Council, Milan, Italy

2Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

3Hematology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

4Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy

5Hematology, Department of Cellular Biotechnologies and Hematology, La Sapienza University, Rome, Italy

6Hematology Unit, Azienda Ospedaliera di Cosenza, Cosenza, Italy

7Hematologic Clinic, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy

8Department of Biomedical Sciences, Division of Hematology, Ospedale Ferrarotto, University of Catania, Catania, Italy

9Hematology Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy

10Department of Hematology, Ospedale S. Eugenio, Tor Vergata University, Rome, Italy

11Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

12Division of Hematology, University of Torino, A.O.U. San Giovanni Battista, Torino, Italy

13Scientific Direction, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy

*These authors have contributed equally to this work

Correspondence to:

Antonino Neri, e-mail: [email protected]

Ingrid Cifola, e-mail: [email protected]

Keywords: whole-exome sequencing, plasma cell leukemia, multiple myeloma, mutations

Received: April 29, 2015     Accepted: May 11, 2015     Published: May 25, 2015


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.

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