Pan-cancer proteogenomic landscape of whole-genome doubling reveals putative therapeutic targets in various cancer types

Abstract

Background: Whole-genome doubling (WGD) is prevalent in cancer and drives tumor development and chromosomal instability. Driver mutations in mitotic cell cycle genes and cell cycle upregulation have been reported as the major molecular underpinnings of WGD tumors. However, the underlying genomic signatures and regulatory networks involved in gene transcription and kinase phosphorylation remain unclear. Here, we aimed to comprehensively decipher the molecular landscape underlying WGD tumors. Methods: We performed a pan-cancer proteogenomic analysis and compared 10 cancer types by integrating genomic, transcriptomic, proteomic, and phosphoproteomic datasets from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). We also integrated the cancer dependency data of each cancer cell line and the survival properties of each cancer patient to propose promising therapeutic targets for patients with WGD. Results: Our study delineated distinct copy number signatures characterizing WGD-positive tumors into three major groups: highly unstable genome, focal instability, and tetraploidy. Furthermore, the analysis revealed the heterogeneous mechanisms underlying WGD across cancer types with specific structural variation patterns. Upregulation of the cell cycle and downregulation of the immune response were found to be specific to certain WGD tumor types. Transcription factors (TFs) and kinases exhibit cancer-specific activities, emphasizing the need for tailored therapeutic approaches. Conclusion: This study introduces an integrative approach to identify potential TF targets for drug development, highlighting BPTF as a promising candidate for the treatment of head and neck squamous cell carcinoma. Additionally, drug repurposing strategies have been proposed, suggesting potential drugs for the treatment of WGD-associated cancers. Our findings offer insights into the heterogeneity of WGD and have implications for precision medicine approaches for cancer treatment.