Abstract 1881: Bimodality in pan-cancer proteomics reveals new biomarker discovery opportunities

Abstract Bimodal protein expression, characterized by a protein distribution with two modes, is linked to phenotypic variation across various biological systems. While previous studies focused on RNA expression data, we developed a bimodality model tailored for proteomics to enhance the identification of cancer-associated biomarkers and targets, facilitating precision oncology. We analyzed proteomics data from various cancer types and identified 2,401 tumor-associated bimodal proteins. These tumor-associated bimodal proteins were evaluated for pathway enrichment, revealing significant associations with critical cancer pathways, such as metabolism of non-essential amino acids, interaction between the extracellular matrix and its receptors on the surface of cells and central carbon metabolism in cancer. Utilizing an AI-enhanced knowledge graph, we further delineated common patterns among pan-cancer tumor-associated bimodal proteins. A case study on the bimodal expression of TROP2 in colon adenocarcinoma highlighted up-regulation of MYC and WNT-beta-catenin signaling pathways and down-regulation of inflammatory and interferon-related pathways in the TROP2-high group. The biological difference between TROP2-high and TROP2-low groups underscored its significance in determining cancer severity and informing potential treatment approaches. Our findings show the utility of proteomics in uncovering novel biomarkers and advancing precision medicine, setting a precedent for further multi-omics integration and clinical validation. Citation Format: Wen Jiang, Damian Bikiel, Jan Zaucha, Jixin Wang, Sanddhya Jayabalan, Yongjin Li, Matthew Sung, James Harper, Jimmy Zhao, Krishna Bulusu, Wenyan Zhong. Bimodality in pan-cancer proteomics reveals new biomarker discovery opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1881.