Multi-omics biomarkers aid prostate cancer prognostication

Abstract

Effective biomarkers and diagnostic tools are urgently needed in clinical settings for improved management of prostate cancer patients, especially to reduce over-treatment of indolent tumors and for early identification of aggressive disease. Gene expression signatures are currently the “gold standard” to provide guide clinical decision, however their clinical utility and interpretability is questionable. Multi-modal molecular profiling provides an holistic approach to systematically unravel the biological complexity underlying cancer pathogenesis, hence biomarkers developed using such an integrated approach hold the potential to more accurately capture cancer-driving alterations than signatures based on a single omics modality. Currently, however, robust and reproducible multi- omics biomarkers are still lacking for prostate cancer. In this study, we analyzed transcriptomics and metabolomics profiles jointly in a prostate cancer cohort and identified two prognostic signatures with high statistical powers (signature 1: EGLN3, succinate, trans-4-hydroxyprolin; and signature 2: IL6, SLC22A2, histamine). Our approach leveraged a priori biological knowledge of the cellular metabolism and gene circuitry, enabling the identification of dysregulated network modules. Functional bioinformatics analyses suggest that these signatures can capture relevant molecular alterations in prostate cancer tissues, including dysregulations of cellular signaling, cell cycle progression, and immune system modulation, stratifying patients in distinct risk groups. Next, we trained two gene expression signatures as a proxy for the multi- omics ones, extending our investigation to publicly available data, further confirming their prognostic values in independent patient cohorts. In summary, the analysis of multi-modal molecular grounded in cellular network biology represents a promising approach for the development of robust prognostic biomarkers of detecting and discriminating high grade disease.