Proteogenomic Landscape of Prospectively Collected Breast Cancer

A persistent central deficiency in our knowledge of cancer concerns how genomic changes drive the proteome and phosphoproteome to execute phenotypic characteristics. Furthermore increasing evidence implicating epigenetic and post-translational changes in cancer biology reinforce the notion that molecular profiles based on nucleic acids are incomplete and are critically complemented by analyses of proteins and their post-translational modifications. We present the first integrated proteogenomic study on a prospectively collected breast cancer cohort, and provide new insights including on taxonomy, metabolic dependencies, and immune milieu. 122 invasive ductal breast cancer samples were collected under the auspices of the National Cancer Institute’s Clinical Proteomics Tumor Analysis Consortium using rigorous protocols to minimize ischemic time and other pre-analytical variability. Samples underwent comprehensive genomic and proteomic characterization, providing whole exome, whole genome, copy number, RNAseq, global proteome, phosphoproteome, and acetylome data. Multi-omics clustering by nonnegative matrix factorization revealed basal-, luminal A-, and HER2-enriched clusters, as well as a combined luminal A/B cluster. Luminal A and A/B clusters were distinguished by differential expression of cytoskeletal signatures possibly driven by YAP1 overexpression and hyper-phosphorylation in the luminal A subset. Kinase outlier analysis revealed luminal A enrichment of PEAK1, an atypical kinase that regulates YAP1 expression. PTPN2, recently shown to synergize with anti-PD1 therapy, was an outlier in basal tumors, suggesting therapeutic opportunities in that difficult-to-treat subtype. Acetylation plays a dominant role in mitochondrial metabolism, and downregulation of deacetylase SIRT3 in basal and HER2-enriched samples was associated with upregulation of TCA cycle- and amino acid metabolism-related proteins suggesting metabolic dependencies that could be exploited. Immunological subtyping of the breast cohort identified immune-cold, immune-hot, immune-excluded and interferon-independent clusters associated with distinct patterns of tumor-infiltrating lymphocytes. Basal tumors generally overexpressed PDL1 relative to other subtypes, whereas the newly described immuno-oncology target SIGLEC15 was overexpressed in luminal tumors. While these and other analyses are intended to provide new insights into breast cancer biology and facilitate testable therapeutic hypotheses, the larger purpose of the program is to provide a resource to the breast cancer and broader scientific communities. To facilitate this, these and previously published data will be integrated to provide a sample set of 199 proteogenomically characterized breast cancers for further exploration. Citation Format: M Gillette, K Krug, S Satpathy, E Jaehnig, A Karpova, K Clauser, L Tang, L Blumenberg, R Kothadia, K Ruggles, B Zhang, L Ding, P Mertins, DR Mani, M Ellis, S Carr. Proteogenomic Landscape of Prospectively Collected Breast Cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr TS1-2.