DNA methylation occurs early in tumorigenesis and is highly pervasive across cancer types, making it suitable for early detection and intervention of cancer. Gene expression at the transcription level is reflected by epigenetic regulation of chromosome especially DNA methylation, therefore providing a distinct approach to achieve the same goal. Noninvasive and real-time gene expression profiling was performed on plasma circulating cell-free mRNA (cfmRNA) enriched from cancer patients using proprietary high sensitivity RT-qPCR assays. A plasma cfmRNA expression database covering 750 genes in 9 major cancer pathways was established with multiple layers of cancer type-specific characteristics: (i) the distribution of cfmRNA species across 9 major cancer pathways; (ii) the differential expression of target genes (high, medium or low expression); (iii) the global cfmRNA expression landscape in circulation; and (iv) the unique cfmRNA signatures to differentiate lung, breast, and pancreatic cancer. These novel blood-based metrics and biomarkers can be deployed for early detection and stratification of cancer.