Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia.

Julie Dubois, Arnon P Kater, Omar Abdel-Wahab, Thorsten Zenz, Andrew Zelenetz, Mark L Heaney, Mark G Frattini, Nicole Lamanna, Tariq Mughal, Vincent Miller, Ross L Levine, Eric Eldering, Christian H Geisler, Marinus H J van Oers, Jan Dürig, Maria Dampmann, Alexander C Leeksma, Koen de Heer, Fransien de Boer, Rainer Claus, Sascha Dietrich, Jennifer Hüllein, Tatjana Walther, Doreen Te Raa, Wendimagegn G Alemayehu, Mithat Gonen, Michelle Nahas, Jie He, Jeffrey R Gardner, Bian Wu, Justin Taylor

Journal: Leukemia 2019;33(2):390-402

PMID: 30038380

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Abstract

Genomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driver genes using targeted next-generation sequencing in 643 CLL patients and found higher frequencies of mutations in TP53 (35 vs. 12%, p < 0.001) and SF3B1 (20 vs. 11%, p < 0.05) and increased number of (sub)clonal (p < 0.0001) mutations in treated patients. We next performed an in-depth evaluation of clonal evolution on untreated CLL patients (50 "progressors" and 17 matched "non-progressors") using a 404 gene-sequencing panel and identified novel mutated genes such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried more mutations at initial presentation (2.5 vs. 1, p < 0.0001). Mutations in specific genes were associated with increased (SF3B1, ATM, and FBXW7) or decreased progression risk (AXIN1 and MYD88). Mutations affecting specific signaling pathways, such as Notch and MAP kinase pathway were enriched in progressive relative to non-progressive patients. These data extend earlier findings that specific genomic alterations and diversity of subclones are associated with disease progression and persistence of disease in CLL and identify novel recurrently mutated genes and associated outcomes.

Address: Department of Hematology and Lymphoma and Myeloma Center Amsterdam, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.; Department of Experimental Immunology, Cancer Center Amsterdam and Infection and Immunity Institute of Amsterdam, Amsterdam, The Netherlands.; Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Department of Molecular Therapy in Haematology & Oncology, German Cancer Research Center (dkfz) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.; Foundation Medicine, Inc., Cambridge, MA, USA.; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; HOVON Data Center, Erasmus MC, Daniel Den Hoedkliniek, Rotterdam, The Netherlands.; Department of Hematology, University Hospital Heidelberg, Heidelberg, Germany.; Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Department of Haematology/Oncology, Augsburg Hospital, Augsburg, Germany.; Department of Internal medicine, Ikazia Hospital, Rotterdam, The Netherlands.; Department of Internal medicine, Flevo Hospital, Almere, The Netherlands.; Department of Haematology, University Hospital Essen, Essen, Germany.; Department of Hematology, Rigshospitalet, Copenhagen, Denmark.; Department of Medicine, Columbia University Medical Center, New York, USA.; Department of Haematology, University Hospital Zürich and University of Zürich, Zürich, Switzerland.; Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].; Department of Hematology and Lymphoma and Myeloma Center Amsterdam, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands. [email protected].; Department of Experimental Immunology, Cancer Center Amsterdam and Infection and Immunity Institute of Amsterdam, Amsterdam, The Netherlands. [email protected].

DOI: 10.1038/s41375-018-0215-9