Cancers can vary greatly in their transcriptomes. In contrast to alterations in specific genes or pathways, the significance of differences in tumor cell total mRNA content is poorly understood. Studies using single-cell sequencing or model systems have suggested a role for total mRNA content in regulating cellular phenotypes. However, analytical challenges related to technical artifacts and cellular admixture have impeded examination of total mRNA expression at scale across cancers. To address this, we evaluated total mRNA expression using single cell sequencing, and developed a computational method for quantifying tumor-specific total mRNA expression (TmS) from bulk sequencing data. We systematically estimated TmS in 5,181 patients across 15 cancer types and observed close correlations with clinicopathologic characteristics and molecular features, where high TmS generally accompanies high-risk disease. At a pan-cancer level, high TmS is associated with increased risk of disease progression and death. Moreover, TmS captures tumor type-specific effects of somatic mutations, chromosomal instability, and hypoxia, as well as aspects of intratumor heterogeneity. Taken together, our results suggest that measuring total mRNA expression offers a broader perspective of tracking cancer transcriptomes, which has important clinical and biological implications. ### Competing Interest Statement A.M. receives royalties for a pancreatic cancer biomarker test from Cosmos Wisdom Biotechnology, and this financial relationship is managed and monitored by the UTMDACC Conflict of Interest Committee. A.M. is also listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection. J.Z. reports research funding from Merck, Johnson and Johnson, and consultant fees from BMS, Johnson and Johnson, AstraZeneca, Geneplus, OrigMed, Innovent outside the submitted work.

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