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Wenyi Wang
The University of Texas MD Anderson Cancer Center
Corresponding Author
ORCiD: https://orcid.org/0000-0003-0617-9438
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Cancers can vary greatly in their transcriptomes. In contrast to alterations in specific genes or pathways, differences in tumor cell total mRNA content have not been comprehensively assessed. Technical and analytical challenges have impeded examination of total mRNA expression at scale across cancers. To address this, we developed a model for quantifying tumor-specific total mRNA expression (TmS) from bulk sequencing data, which performs transcriptomic deconvolution while adjusting for mixed genomes. We used single-cell RNA sequencing data to demonstrate total mRNA expression as a feature of tumor phenotype. We estimated and validated TmS in 5,015 patients across 15 cancer types identifying significant inter-individual variability. At a pan-cancer level, high TmS is associated with increased risk of disease progression and death. Cancer type-specific patterns of genetic alterations, intra-tumor genetic heterogeneity, as well as pan-cancer trends in metabolic dysregulation and hypoxia contribute to TmS. Taken together, our results suggest that measuring cell-type specific total mRNA expression offers a broader perspective of tracking cancer transcriptomes, which has important biological and clinical implications.
Keywords
cancer, tumor cell mRNA, phenotype
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The full text of this article is available to read as a PDF.
Yes there is potential Competing Interest. 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. P.M. has received honoraria for service on a Scientific Advisory Board for Mirati Therapeutics and BMS, non-branded educational programs supported by Exelixis and Pfizer, and research funding for clinical trials from Takeda, BMS, Mirati Therapeutics, Gateway for Cancer Research, and UT MD Anderson Cancer Center, all outside the submitted work.
This is a list of supplementary files associated with this preprint. Click to download.
- TmSSupplementaryNotecompressed.pdf
Supplementary Note
- SupplementaryTables.pdf
Supplementary Tables
- SupplementalFigures.pdf
Supplementary Figures
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This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
Wenyi Wang
The University of Texas MD Anderson Cancer Center
Corresponding Author
ORCiD: https://orcid.org/0000-0003-0617-9438
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 11 Jun, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Cancers can vary greatly in their transcriptomes. In contrast to alterations in specific genes or pathways, differences in tumor cell total mRNA content have not been comprehensively assessed. Technical and analytical challenges have impeded examination of total mRNA expression at scale across cancers. To address this, we developed a model for quantifying tumor-specific total mRNA expression (TmS) from bulk sequencing data, which performs transcriptomic deconvolution while adjusting for mixed genomes. We used single-cell RNA sequencing data to demonstrate total mRNA expression as a feature of tumor phenotype. We estimated and validated TmS in 5,015 patients across 15 cancer types identifying significant inter-individual variability. At a pan-cancer level, high TmS is associated with increased risk of disease progression and death. Cancer type-specific patterns of genetic alterations, intra-tumor genetic heterogeneity, as well as pan-cancer trends in metabolic dysregulation and hypoxia contribute to TmS. Taken together, our results suggest that measuring cell-type specific total mRNA expression offers a broader perspective of tracking cancer transcriptomes, which has important biological and clinical implications.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
The full text of this article is available to read as a PDF.
Yes there is potential Competing Interest. 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. P.M. has received honoraria for service on a Scientific Advisory Board for Mirati Therapeutics and BMS, non-branded educational programs supported by Exelixis and Pfizer, and research funding for clinical trials from Takeda, BMS, Mirati Therapeutics, Gateway for Cancer Research, and UT MD Anderson Cancer Center, all outside the submitted work.
This is a list of supplementary files associated with this preprint. Click to download.
- TmSSupplementaryNotecompressed.pdf
Supplementary Note
- SupplementaryTables.pdf
Supplementary Tables
- SupplementalFigures.pdf
Supplementary Figures
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