title: DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features.
abstract: Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation.
authors.affiliation: Lymphoma & Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland;
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Arribas
authors.affiliation: Lymphoma & Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland;
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Lymphoma & Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland;
authors.forename: Afua A
authors.initials: AA
authors.lastname: Mensah
authors.affiliation: Lymphoma & Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland; Dalle Molle Institute for Artificial Intelligence, Manno, Switzerland;
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
authors.affiliation: Lymphoma & Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
authors.forename: Luciano
authors.identifier: http://orcid.org/0000-0002-4606-0637
authors.initials: L
authors.lastname: Cascione
authors.affiliation: Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain;
authors.forename: Eloy F
authors.initials: EF
authors.lastname: Robles
authors.affiliation: Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain;
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Climent
authors.affiliation: Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.affiliation: Division of Hematology, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, Pavia, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Arcaini
authors.affiliation: Hematology/Bone Marrow Transplantation Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Baldini
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: Hematology Laboratory and Service d'Hemato-oncologie, Hopitaé Saint-Louis, Université Paris Diderot, Paris, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Thieblemont
authors.affiliation: Hematology Laboratory and Service d'Hemato-oncologie, Hopitaé Saint-Louis, Université Paris Diderot, Paris, France;
authors.forename: Josette
authors.initials: J
authors.lastname: Briere
authors.affiliation: Haematology Oncology Group, Cancer Sciences Unit, Cancer Research UK Centre, University of Southampton and Haematology Department, Southampton University Hospital Trust, Southampton, United Kingdom; Division of Haematology, University of Siena, Siena, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Departments of Pathology and Hematology, University of Verona, Verona, Italy;
authors.forename: Alberto
authors.initials: A
authors.lastname: Zamò
authors.affiliation: Departments of Pathology and Hematology, University of Verona, Verona, Italy;
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonifacio
authors.affiliation: Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain;
authors.forename: Manuela
authors.initials: M
authors.lastname: Mollejo
authors.affiliation: Department of Pathology, University of Brescia, I Servizio di Anatomia Patologica, Spedali Civili di Brescia, Brescia, Italy;
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.affiliation: Institute of Pathology, University of Basel, Basel, Switzerland;
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Pathology Unit and Unit of Lymphoid Malignancies, San Raffaele H Scientific Institute, Milan, Italy;
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY;
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Department of Pathology, Hospital Marques de Valdecilla, Santander, Spain; and.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Lymphoma & Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
authors.forename: Francesco
authors.identifier: http://orcid.org/0000-0001-5637-8983
authors.initials: F
authors.lastname: Bertoni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016000:Cluster Analysis; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D000090062:Kruppel-Like Factor 4; D018442:Lymphoma, B-Cell, Marginal Zone / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013160:Splenic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D016896:Treatment Outcome