Functional Proteogenomics Reveals Biomarkers and Therapeutic Targets in Lymphomas

The proteomic and posttranslational modification signatures of most cancers are unknown. N-linked glycosylation is a post-translational modification that targets proteins for membrane expression or secretion making this class of proteins attractive cancer biomarkers and therapeutic targets. Using an unbiased mass spectrometry (MS)-based approach we generated a compendium of 1,155 N-linked glycoproteins (2,160 N-glycosites) from 44 human primary lymphomas and malignant lymphoma cell lines. Hierarchical clustering highlighted distinct subtype signatures which included several novel subtype-specific biomarkers. Orthogonal immunologic studies in 671 primary lymphoma tissue biopsies, 36 lymphoma-derived cell lines or 8 patient-derived circulating tumor cell samples corroborated MS-based glycoproteomic data and authenticated selected proteins as tissue biomarkers. Functional targeting using a toxin-conjugated ligand in vitro and RNAi-mediated silencing targeting subtype-specific glycoproteins abrogated lymphoma growth in vivo. Our results demonstrate the utility of global N-glycoproteomics discovery of cancer biomarkers and targets for precision therapeutics.