The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

1st Department of Propaedeutic Medicine University of Athens Athens Greece

Central European Institute of Technology Masaryk University Brno Czech Republic

Centre for Cancer Research and Cell Biology Queen's University Belfast Belfast UK

Department of Haematology Athens Medical Center Athens Greece

Department of Haematology Royal Bournemouth Hospital Bournemouth UK

Department of Haematology University of Crete Heraklion Greece

Department of Hematology Hopital Pitie Salpetriere and Sorbonne University Paris France

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Informatics Ionian University Corfu Greece

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Pathology and Hematology Hospices Civils de Lyon Universite Lyon 1 Lyon France

Department of Pathology Hopital Pitie Salpetriere and Sorbonne University Paris France

Department of Pathology Radboud University Medical Center Nijmegen The Netherlands

Direzione Scientifica Istituto di Ricovero e Cura a Carattere Scientifico San Martino IST Genoa Italy

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge UK

Division of Experimental Oncology and Department of Onco Hematology IRCCS San Raffaele Scientific Institute and Università Vita Salute San Raffaele Milan Italy

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department Nikea General Hospital Piraeus Greece

Hematopathology Department Evangelismos Hospital Athens Greece

Hospital Virgen de la Salud Toledo Spain

IMGT® the international ImMunoGeneTics Information System® Université de Montpellier LIGM Institut de Génétique Humaine IGH UMR CNRS UM Montpellier France

Information Technologies Institute CERTH Thessaloniki Greece

Information Technologies Institute CERTH Thessaloniki Greece Department of Informatics Ionian University Corfu Greece

Institute of Applied Biosciences CERTH Thessaloniki Greece

Institute of Applied Biosciences CERTH Thessaloniki Greece Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Laboratori de Citologia Hematològica i Citogenètica Molecular Servei de Patologia Hospital del Mar Barcelona Spain

Molecular Pathology Ospedale Policlinico SanMartino Genoa Italy

Pathology Department IIS 'Fundacion Jimenez Diaz' Madrid Spain

Pathology Unit San Raffaele Scientific Institute Milan Italy

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$a The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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