Genomic determinants of protein abundance variation in colorectal cancer cells

Summary Assessing the extent to which genomic alterations compromise the integrity of the proteome is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labelling and tribrid mass spectrometry to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the relationships between genomic and proteomic variation. The robust quantification of 12,000 proteins and 27,000 phosphopeptides revealed how protein symbiosis translates to a co-variome which is subjected to a hierarchical order and exposes the collateral effects of somatic mutations on protein complexes. Targeted depletion of key chromatin modifiers confirmed the transmission of variation and the directionality as characteristics of protein interactions. Protein level variation was leveraged to build drug response predictive models towards a better understanding of pharmacoproteomic interactions in colorectal cancer. Overall, we provide a deep integrative view of the molecular structure underlying the variation of colorectal cancer cells. Highlights The cancer cell functional “co-variome” is a strong attribute of the proteome. Mutations can have a direct impact on protein levels of chromatin modifiers. Transmission of genomic variation is a characteristic of protein interactions. Pharmacoproteomic models are strong predictors of response to DNA damaging agents. Abbreviations COREAD Colorectal Adenocarcinoma IMAC Immobilized Metal ion Affinity Chromatography ROC Receiver Operating Characteristic AUC Area Under the Curve WGCNA Weighted Correlation Network Analysis CNA Copy Number Alteration SOM Self-Organizing Map QTL Quantitative Trait Loci MSI Microsatellite Instability CPS Colorectal Proteomic Subtypes