Proteogenomics refines the molecular classification of chronic lymphocytic leukemia.

Sophie A Herbst, Mattias Vesterlund, Alexander J Helmboldt, Rozbeh Jafari, Ioannis Siavelis, Matthias Stahl, Eva C Schitter, Nora Liebers, Berit J Brinkmann, Felix Czernilofsky, Tobias Roider, Peter-Martin Bruch, Murat Iskar, Adam Kittai, Ying Huang, Junyan Lu, Sarah Richter, Georgios Mermelekas, Husen Muhammad Umer, Mareike Knoll, Carolin Kolb, Angela Lenze, Xiaofang Cao, Cecilia Österholm, Linus Wahnschaffe, Carmen Herling, Sebastian Scheinost, Matthias Ganzinger, Larry Mansouri, Katharina Kriegsmann, Mark Kriegsmann, Simon Anders, Marc Zapatka, Giovanni Del Poeta, Antonella Zucchetto, Riccardo Bomben, Valter Gattei, Peter Dreger, Jennifer Woyach, Marco Herling, Carsten Müller-Tidow, Richard Rosenquist, Stephan Stilgenbauer, Thorsten Zenz, Wolfgang Huber, Eugen Tausch, Janne Lehtiö, Sascha Dietrich

Journal: Nature communications 2022;13(1):6226

PMID: 36266272

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Abstract

Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic-based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterize the proteome and transcriptome alongside genetic and ex-vivo drug response profiling in a clinically annotated CLL discovery cohort (n = 68). Unsupervised clustering of the proteome data reveals six subgroups. Five of these proteomic groups are associated with genetic features, while one group is only detectable at the proteome level. This new group is characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). Classifiers developed to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n = 165, n = 169) confirm that ASB-CLL comprises about 20% of CLL patients. The inferior overall survival in ASB-CLL is also independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling.

Address: Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.; Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.; Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.; Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf (CIO ABCD), Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany.; Institute of Pathology, University of Heidelberg, Heidelberg, Germany.; Center for Molecular Biology of the University of Heidelberg (ZMBH), Heidelberg, Germany.; Division of Hematology, University of Tor Vergata, Rome, Italy.; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.; Department of Internal Medicine III, University of Ulm, Ulm, Germany.; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.; Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden. [email protected].; Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany. [email protected].; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. [email protected].; Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany. [email protected].; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].; Department of Hematolgy, Oncology and Immunolgy, University Hospital of Düsseldorf, Düsseldorf, Germany. [email protected].

DOI: 10.1038/s41467-022-33385-8

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https://assays.cancer.gov/CPTAC-951

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https://antibodies.cancer.gov/detail/CPTC-TP53-2

MeSH Terms: Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Proteomics, Proteogenomics, Proteome, Mutation, Receptors, Antigen, B-Cell