Integrated Proteogenomic Analysis Reveals Distinct Potentially Actionable Therapeutic Vulnerabilities in Triple-Negative Breast Cancer Subtypes

Simple Summary Despite the significant progress made in precision oncology and genetic analysis, there are few effective treatment options available for triple-negative breast cancer (TNBC). Developing successful treatment approaches for TNBC requires the exploitation of therapeutic vulnerabilities using a multi-dimensional framework. In this study, we analyzed protein data from the Cancer Genome Atlas (TCGA) dataset by integrating it with DNA and RNA sequencing. By working backwards from protein to RNA to DNA, we identified copy number alterations as the key genomic drivers over mutations, and therefore copy number alterations represent important potential therapeutic targets in TNBC. Our multi-omics approach aids in the identification of potentially predictive alterations in TNBC, bringing us closer to precision medicine for this aggressive disease.Abstract Triple-negative breast cancer (TNBC) is characterized by an aggressive clinical presentation and a paucity of clinically actionable genomic alterations. Here, we utilized the Cancer Genome Atlas (TCGA) to explore the proteogenomic landscape of TNBC subtypes to see whether genomic alterations can be inferred from proteomic data. We found only 4% of the protein level changes are explained by mutations, while 21% of the protein and 35% of the transcriptomics changes were determined by copy number alterations (CNAs). We found tighter coupling between proteome and genome in some genes that are predicted to be the targets of drug inhibitors, including CDKs, PI3K, tyrosine kinase (TKI), and mTOR. The validation of our proteogenomic workflow using mass spectrometry Clinical Proteomic Tumor Analysis Consortium (MS-CPTAC) data also demonstrated the highest correlation between protein-RNA-CNA. The integrated proteogenomic approach helps to prioritize potentially actionable targets and may enable the acceleration of personalized cancer treatment.