Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.
Bibliographical noteFunding Information:
The work was supported by TRANSCAN/Dutch Cancer Society grant (179; NOVEL Consortium); Directorate General for Health and Consumer Protection of the European Commission (DG-SANCO); International Agency for Research on Cancer, Danish Cancer Society (Denmark); Ligue Natinale Contre le Cancer; Institut Gustave Roussy; Mutuelle Generale de l'Education Nationale, INSERM (France); German Cancer Aid; German Cancer Research Center; Federal Ministry of Education and Research; German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro (AIRC)Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports; Netherlands Cancer Registry; LK Research Funds; Dutch Prevention Funds; Dutch Zorg Onderzoek Nederland; World Cancer Research Fund; Statistics Netherlands (The Netherlands), grant ERC2009-AdG 232997; Nordforsk; Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway); German Federal Ministry of Education and Research (BMBF 01EO1303); Centro de Investigación Biomédica en Red: Epidemiologíay Pública (Spain); Spanish Ministry of Economy and Competitiveness -Carlos III Institute of Health cofunded by the European Regional Development Fund - a way to build Europe, grants PI13/00061 (to Granada), PI13/01162 (to EPIC-Murcia, Regional Governments of Andalucıa, Asturias, Basque Country, Murcia, and Navarra), and PI17/01280 and PI14/01219 (to Barcelona); Agència de Gestió d'Ajuts Universitaris i de Recerca; Centres de Recerca de Catalunya (CERCA) Programme/Generalitat de Catalunya for institutional support, grant 2017SGR1085; Swedish Cancer Society; Swedish Research Council and County Councils of Skåne and Vasterbotten (Sweden); Cancer Research UK, grants 14136 (to EPIC-Norfolk) and C570/A11692, C570/A16491, and C8221/A19170 (to EPIC-Oxford); Medical Research Council, grants 1000143 (to EPIC-Norfolk) and MR/M012190/1 (to EPIC-Oxford, United Kingdom); and the Hellenic Foundation for Research and Innovation and the General Secretariat for Research and Technology under grant agreement 336 (Project CLLon).
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