title: The genetics of nodal marginal zone lymphoma.
abstract: Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, whole-transcriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinicopathologic entity within the current lymphoma classification.
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
authors.forename: Valeria
authors.initials: V
authors.lastname: Spina
authors.affiliation: Department of Biomedical Informatics and Systems Biology, Columbia University, New York, NY;
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Monti
authors.affiliation: Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
authors.forename: Alessio
authors.initials: A
authors.lastname: Bruscaggin
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Spaccarotella
authors.affiliation: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY;
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.affiliation: Department of Hematology-Oncology, Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Arcaini
authors.affiliation: Division of Pathology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Lucioni
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tabbò
authors.affiliation: Department of Biomedical Informatics and Systems Biology, Columbia University, New York, NY;
authors.forename: Sakellarios
authors.initials: S
authors.lastname: Zairis
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
authors.forename: Fary
authors.initials: F
authors.lastname: Diop
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
authors.forename: Michaela
authors.initials: M
authors.lastname: Cerri
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.affiliation: Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.affiliation: Ateneo Vita-Salute and Unit of Lymphoid Malignancies, San Raffaele H. Scientific Institute, Milan, Italy;
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Department of Medical Sciences, University of Torino and Immunogenetics Unit, Human Genetics Foundation, Torino, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.affiliation: Division of Pathology, Department of Health Sciences, Amedeo Avogadro University of Eastern Piedmont and Maggiore Hospital, Novara, Italy;
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramponi
authors.affiliation: Institute of Hematology, Ospedale S. Maria della Misericordia, University of Perugia, Perugia, Italy;
authors.forename: Enrico
authors.initials: E
authors.lastname: Tiacci
authors.affiliation: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY;
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.affiliation: Division of Pathology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Paulli
authors.affiliation: Institute of Hematology, Ospedale S. Maria della Misericordia, University of Perugia, Perugia, Italy;
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY; Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, Torino, Italy; and Department of Pathology, NYU Cancer Center, New York University School of Medicine, New York, NY.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.affiliation: Department of Biomedical Informatics and Systems Biology, Columbia University, New York, NY;
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D051883:Receptor, Notch2 / Q000235:genetics*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D013160:Splenic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C497764:NOTCH2 protein, human; D051883:Receptor, Notch2; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2