title: Machine Learning-based Classification of Diffuse Large B-cell Lymphoma Patients by Their Protein Expression Profiles.
abstract: Characterization of tumors at the molecular level has improved our knowledge of cancer causation and progression. Proteomic analysis of their signaling pathways promises to enhance our understanding of cancer aberrations at the functional level, but this requires accurate and robust tools. Here, we develop a state of the art quantitative mass spectrometric pipeline to characterize formalin-fixed paraffin-embedded tissues of patients with closely related subtypes of diffuse large B-cell lymphoma. We combined a super-SILAC approach with label-free quantification (hybrid LFQ) to address situations where the protein is absent in the super-SILAC standard but present in the patient samples. Shotgun proteomic analysis on a quadrupole Orbitrap quantified almost 9,000 tumor proteins in 20 patients. The quantitative accuracy of our approach allowed the segregation of diffuse large B-cell lymphoma patients according to their cell of origin using both their global protein expression patterns and the 55-protein signature obtained previously from patient-derived cell lines (Deeb, S. J., D'Souza, R. C., Cox, J., Schmidt-Supprian, M., and Mann, M. (2012) Mol. Cell. Proteomics 11, 77-89). Expression levels of individual segregation-driving proteins as well as categories such as extracellular matrix proteins behaved consistently with known trends between the subtypes. We used machine learning (support vector machines) to extract candidate proteins with the highest segregating power. A panel of four proteins (PALD1, MME, TNFAIP8, and TBC1D4) is predicted to classify patients with low error rates. Highly ranked proteins from the support vector analysis revealed differential expression of core signaling molecules between the subtypes, elucidating aspects of their pathobiology.
authors: From the ‡Proteomics and Signal Transduction Group and.
authors: Sally J
authors: SJ
authors: Deeb
authors: From the ‡Proteomics and Signal Transduction Group and §Computational Systems Biochemistry, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.
authors: Stefka
authors: S
authors: Tyanova
authors: ¶Institute of Pathology, Campus Benjamin Franklin, Molecular Diagnostics, Charité-Universitätsmedizin Berlin, 12200 Berlin, Germany, and.
authors: Michael
authors: M
authors: Hummel
authors: ‖Institute of Oncology and Hematology, III. Medizinische Klinik, Technische Universität München, 81675 Munich, Germany.
authors: Marc
authors: M
authors: Schmidt-Supprian
authors: §Computational Systems Biochemistry, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.
authors: Juergen
authors: J
authors: Cox
authors: From the ‡Proteomics and Signal Transduction Group and mmann@biochem.mpg.de.
authors: Matthias
authors: M
authors: Mann
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005557:Formaldehyde; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000069550:Machine Learning; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction; D016610:Tissue Embedding; D016707:Tissue Fixation
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D020690:GTPase-Activating Proteins; D009363:Neoplasm Proteins; D020543:Proteome; C518767:TBC1D4 protein, human; C404190:TNFAIP8 protein, human; D005557:Formaldehyde; C546583:PALD1 protein, human; D010749:Phosphoprotein Phosphatases; D015260:Neprilysin