Proteogenomics represents a transformative approach in cancer research that bridges the gap between genomic alterations and their functional consequences at the protein level. While genomic sequencing has revolutionized our understanding of cancer biology, it remains limited in predicting actual protein expression levels, post-translational modifications, and downstream functional effects. This is particularly problematic given that most modern cancer therapies target proteins rather than genes directly.

The foundation of proteogenomics lies in the integration of multi-omics data—genomics, transcriptomics, proteomics, and phosphoproteomics—to create a comprehensive molecular portrait of tumors. Mass spectrometry-based proteomics has emerged as the cornerstone technology enabling this integration. Recent advances in MS instrumentation, sample preparation, and data analysis have dramatically improved the depth and accuracy of proteomic measurements, now allowing quantification of thousands of proteins and PTMs from tumor specimens.

One of the key insights from proteogenomic studies is the frequently observed discordance between mRNA and protein levels. While transcriptomics provides valuable information about gene expression, it often fails to capture the regulatory events occurring at the translational and post-translational levels. Proteogenomics addresses this limitation by directly measuring the effector molecules—proteins—that execute cellular functions and serve as therapeutic targets.

Post-translational modifications, particularly phosphorylation, represent a critical layer of regulation that cannot be inferred from genomic data alone. Phosphoproteomics enables systematic characterization of signaling pathway activation states, revealing drug targets and resistance mechanisms that would remain hidden through genomic analysis. The integration of phosphoproteomic data with genomic alterations has identified novel kinase-substrate relationships and pathway dependencies in various cancer types.

The clinical utility of proteogenomics is increasingly being demonstrated across multiple cancer types. In breast cancer, proteogenomic subtyping has refined our understanding of disease heterogeneity beyond traditional genomic classifications. In colorectal cancer, proteogenomic analyses have revealed distinct molecular subtypes with therapeutic implications. Similar insights have emerged from studies of ovarian, lung, and head and neck cancers, among others.

Looking forward, proteogenomics is poised to play an expanding role in precision oncology. Ongoing efforts aim to standardize proteomic workflows for clinical applications, develop targeted proteomic assays for therapeutic monitoring, and integrate proteogenomic data into clinical trial design. The combination of proteogenomics with emerging technologies such as single-cell analysis and spatial proteomics promises to further enhance our understanding of tumor biology and improve patient outcomes.
DOI
10.1007/s11684-026-1222-2