OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine

• Published in: Scientific reports Vol. 10; no. 1; p. 5285
• Main Authors: López-Cortés, Andrés, Paz-y-Miño, César, Guerrero, Santiago, Cabrera-Andrade, Alejandro, Barigye, Stephen J., Munteanu, Cristian R., González-Díaz, Humberto, Pazos, Alejandro, Pérez-Castillo, Yunierkis, Tejera, Eduardo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.03.2020; Nature Publishing Group
• Subjects: 38; 631/67/1347; 631/67/69; 692/4017; AKT1 protein; Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Clinical trials; Cyclin-dependent kinase 2; Doxorubicin; Drug development; E-cadherin; Epidermal growth factor receptors; ErbB-2 protein; Female; GATA-3 protein; Gene Expression Regulation, Neoplastic; Gene mapping; Gene Regulatory Networks; Genes, Essential; Grb2 protein; Heterogeneity; High-Throughput Nucleotide Sequencing; Humanities and Social Sciences; Humans; Mice; Monoclonal antibodies; mRNA; multidisciplinary; Mutation; Oncology; p53 Protein; Paclitaxel; Precision Medicine; Prognosis; Protein Interaction Maps; Proteins; Proteome; Rac1 protein; Science; Science (multidisciplinary); Signal transduction; Tamoxifen; Targeted cancer therapy; Therapeutic applications; Trastuzumab; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-62279-2

Breast cancer (BC) is the leading cause of cancer-related death among women and the most commonly diagnosed cancer worldwide. Although in recent years large-scale efforts have focused on identifying new therapeutic targets, a better understanding of BC molecular processes is required. Here we focused on elucidating the molecular hallmarks of BC heterogeneity and the oncogenic mutations involved in precision medicine that remains poorly defined. To fill this gap, we established an OncoOmics strategy that consists of analyzing genomic alterations, signaling pathways, protein-protein interactome network, protein expression, dependency maps in cell lines and patient-derived xenografts in 230 previously prioritized genes to reveal essential genes in breast cancer. As results, the OncoOmics BC essential genes were rationally filtered to 140. mRNA up-regulation was the most prevalent genomic alteration. The most altered signaling pathways were associated with basal-like and Her2-enriched molecular subtypes. RAC1 , AKT1 , CCND1 , PIK3CA , ERBB2 , CDH1 , MAPK14 , TP53 , MAPK1 , SRC , RAC3 , BCL2 , CTNNB1 , EGFR , CDK2 , GRB2 , MED1 and GATA3 were essential genes in at least three OncoOmics approaches. Drugs with the highest amount of clinical trials in phases 3 and 4 were paclitaxel, docetaxel, trastuzumab, tamoxifen and doxorubicin. Lastly, we collected ~3,500 somatic and germline oncogenic variants associated with 50 essential genes, which in turn had therapeutic connectivity with 73 drugs. In conclusion, the OncoOmics strategy reveals essential genes capable of accelerating the development of targeted therapies for precision oncology.