Multiomic liquid biopsy: emerging applications in disease quantification, biomarker detection, molecular phenotyping, and cancer signal of origin prediction

The field of cancer-related liquid biopsy, largely defined as plasma circulating tumor DNA (ctDNA) analysis by next-generation sequencing (NGS), is rapidly evolving from genomics-only approaches to multiomic assays that add components such as DNA fragmentomics and epigenomics, with or without proteomics, to a genomic backbone. Here we describe how integration of epigenomic profiling, particularly tumor-specific methylation signatures, may extend ctDNA testing beyond detection of genomic alterations toward broader molecular phenotyping, with applications in alternative approaches to tumor fraction quantification, enhanced detection of actionable genomic biomarkers and mechanisms of resistance, histologic and lineage characterization, and cancer signal of origin prediction. This evolution has facilitated the clinical application of liquid biopsy across the cancer care continuum, from screening/early detection to determining minimal residual disease (MRD) in early-stage cancers to selecting treatment and determining mechanisms of acquired resistance in advanced-stage cancers. These new multiomic assays may also support prospective biomarker-driven clinical trials incorporating complementary measures of tumor burden, genomic alterations, and molecular phenotype. Collectively, these advances suggest that multiomic liquid biopsy platforms may represent a major advance in precision oncology, enabling dynamic and comprehensive characterization of tumor biology.