TY - JOUR
T1 - Whole-exome sequencing of primary plasma cell leukemia discloses heterogeneous mutational patterns
AU - Cifola, Ingrid
AU - Lionetti, Marta
AU - Pinatel, Eva
AU - Todoerti, Katia
AU - Mangano, Eleonora
AU - Pietrelli, Alessandro
AU - Fabris, Sonia
AU - Mosca, Laura
AU - Simeon, Vittorio
AU - Petrucci, Maria Teresa
AU - Morabito, Fortunato
AU - Offidani, Massimo
AU - di Raimondo, Francesco
AU - Falcone, Antonietta
AU - Caravita, Tommaso
AU - Battaglia, Cristina
AU - de Bellis, Gianluca
AU - Palumbo, Antonio
AU - Musto, Pellegrino
AU - Neri, Antonino
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Multiple myeloma
KW - Mutations
KW - Plasma cell leukemia
KW - Whole-exome sequencing
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M3 - Article
AN - SCOPUS:84938281756
VL - 6
SP - 17543
EP - 17558
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 19
ER -