Large-Scale Plasma Proteome Epitome Profiling is an Efficient Tool for the Discovery of Cancer Biomarkers

Jozsef Lazar, Peter Antal-Szalmas, Istvan Kurucz, Annamaria Ferenczi, Mihaly Jozsi, Ilona Tornyi, Monika Muller, Janos Tibor Fekete, John Lamont, Peter FitzGerald, Anna Gall-Debreceni, Janos Kadas, Andras Vida, Nadege Tardieu, Yann Kieffer, Anne Jullien, Mariana Guergova-Kuras, William Hempel, Andras Kovacs, Tamas KardosNora Bittner, Eszter Csanky, Maria Szilasi, Gyorgy Losonczy, Klara Szondy, Gabriella Galffy, Edit Csada, Klara Szalontai, Attila Somfay, David Malka, Paul Cottu, Krisztina Bogos, Laszlo Takacs

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Current proteomic technologies focus on the quantification of protein levels, while little effort is dedicated to the development of system approaches to simultaneously monitor proteome variability and abundance. Protein variants may display different immunogenic epitopes detectable by monoclonal antibodies. Epitope variability results from alternative splicing, posttranslational modifications, processing, degradation, and complex formation and possesses dynamically changing availability of interacting surface structures that frequently serve as reachable epitopes and often carry different functions. Thus, it is highly likely that the presence of some of the accessible epitopes correlates with function under physiological and pathological conditions. To enable the exploration of the impact of protein variation on the immunogenic epitome first, here, we present a robust and analytically validated PEP technology for characterizing immunogenic epitopes of the plasma. To this end, we prepared mAb libraries directed against the normalized human plasma proteome as a complex natural immunogen. Antibody producing hybridomas were selected and cloned. Monoclonal antibodies react with single epitopes, thus profiling with the libraries is expected to profile many epitopes which we define by the mimotopes, as we present here. Screening blood plasma samples from control subjects (n = 558) and cancer patients (n = 598) for merely 69 native epitopes displayed by 20 abundant plasma proteins resulted in distinct cancer-specific epitope panels that showed high accuracy (AUC 0.826–0.966) and specificity for lung, breast, and colon cancer. Deeper profiling (≈290 epitopes of approximately 100 proteins) showed unexpected granularity of the epitope-level expression data and detected neutral and lung cancer–associated epitopes of individual proteins. Biomarker epitope panels selected from a pool of 21 epitopes of 12 proteins were validated in independent clinical cohorts. The results demonstrate the value of PEP as a rich and thus far unexplored source of protein biomarkers with diagnostic potential.

Original languageEnglish
Article number100580
JournalMolecular and Cellular Proteomics
Volume22
Issue number7
DOIs
StatePublished - Jul 2023
Externally publishedYes

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