Abstract
Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.
| Original language | English |
|---|---|
| Pages (from-to) | 1624–1633 |
| Journal | Nature Biotechnology |
| Volume | 40 |
| Issue number | 11 |
| Early online date | 2022 |
| DOIs | |
| Publication status | Published - 2022 |
| Publication type | A1 Journal article-refereed |
Publication forum classification
- Publication forum level 3
ASJC Scopus subject areas
- Biotechnology
- Bioengineering
- Biomedical Engineering
- Applied Microbiology and Biotechnology
- Molecular Medicine
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In: Nature Biotechnology, Vol. 40, No. 11, 2022, p. 1624–1633.
Research output: Contribution to journal › Article › Scientific › peer-review
TY - JOUR
T1 - Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression
AU - Cao, Shaolong
AU - Wang, Jennifer R.
AU - Ji, Shuangxi
AU - Yang, Peng
AU - Dai, Yaoyi
AU - Guo, Shuai
AU - Montierth, Matthew D.
AU - Shen, John Paul
AU - Zhao, Xiao
AU - Chen, Jingxiao
AU - Lee, Jaewon James
AU - Guerrero, Paola A.
AU - Spetsieris, Nicholas
AU - Engedal, Nikolai
AU - Taavitsainen, Sinja
AU - Yu, Kaixian
AU - Livingstone, Julie
AU - Bhandari, Vinayak
AU - Hubert, Shawna M.
AU - Daw, Najat C.
AU - Futreal, P. Andrew
AU - Efstathiou, Eleni
AU - Lim, Bora
AU - Viale, Andrea
AU - Zhang, Jianjun
AU - Nykter, Matti
AU - Czerniak, Bogdan A.
AU - Brown, Powel H.
AU - Swanton, Charles
AU - Msaouel, Pavlos
AU - Maitra, Anirban
AU - Kopetz, Scott
AU - Campbell, Peter
AU - Speed, Terence P.
AU - Boutros, Paul C.
AU - Zhu, Hongtu
AU - Urbanucci, Alfonso
AU - Demeulemeester, Jonas
AU - Van Loo, Peter
AU - Wang, Wenyi
N1 - Funding Information: S.C. is supported by the Norman Jaffe Professorship in Pediatrics Endowment Fund, the MD Anderson Colorectal Cancer Moon Shot Program and National Institutes of Health (NIH) R01CA183793. J.R.W. is supported by an American Thyroid Association/ThyCa grant, a Mark Foundation for Cancer Research ASPIRE award and the Michael Petrick Anaplastic Thyroid Cancer Research Fund. S.J. is supported by Human Cell Atlas Seed Network-Retina by the Chan Zuckerberg Institute, the MD Anderson Colorectal Cancer Moon Shot Program, NIH R01CA183793 and Cancer Prevention and Research Institute of Texas (CPRIT) RP200383. P.Y. and M.D.M. are supported by NIH R01CA239342. S.G. is supported by Human Cell Atlas Seed Network-Retina by the Chan Zuckerberg Institute and the MD Anderson Prostate Cancer Moon Shot Program. J.C. is supported by NIH R01CA158113. J.P.S. was supported by National Cancer Institute (NCI) L30 CA171000, K22 CA234406 and P50CA221707, CPRIT RR180035 (to J.P.S.; J.P.S. is a CPRIT Scholar in Cancer Research) and the Col. Daniel Connelly Memorial Fund. J.J.L. is supported by NIH T32CA009599. S.T. and M.N. are supported by The Academy of Finland, the Cancer Society of Finland, the Sigrid Juselius Foundation and the Finnish Cultural Foundation. N.C.D. is supported by the Norman Jaffe Professorship in Pediatrics Endowment Fund. P.A.F. is supported, in part, by the Welch Foundation, MEI Pharma, Inc., Cancer Research United Kingdom (CRUK), the Kadoorie Charitable Foundation and NIH/NCI U01 CA224044 and R01CA231465. B.L is supported by the SWOG Hope Foundation, the Human Cell Atlas-Breast by the Chan Zuckerberg Institute, the US Department of Defense, the Breast Cancer Research Foundation and the NIH. P.M. is supported by a Career Development Award from the American Society of Clinical Oncology, a Research Award from KCCure, the MD Anderson Khalifa Scholar Award and the MD Anderson Physician-Scientist Award. P.C.B. is supported by NIH/NCI P30CA016042, 1U01CA214194-01 and 1U24CA248265-01. A.U. and N.E. are supported by the Norwegian Cancer Society (198016-2018). J.Z. is supported by the MD Anderson Physician-Scientist Award, the MD Anderson Lung Cancer Moon Shot Program, NIH/NCI R01CA234629-01 and U01-CA256780-01 and a CPRIT Multi-Investigator Research Award grant (RP160668). A.M. is supported by the MD Anderson Pancreatic Cancer Moon Shot Program, the Khalifa Bin Zayed Al-Nahyan Foundation and NIH U01CA196403, U01CA200468, U24CA224020 and P50CA221707. S.K. is supported by NIH P50CA221707. C.S. is the Royal Society Napier Research Professor (RSRP\R\210001). This work was supported by the Francis Crick Institute, which receives its core funding from CRUK (FC001169), the UK Medical Research Council (FC001169) and the Wellcome Trust (FC001169). This research was funded in part by the Wellcome Trust (FC001169). For the purpose of open access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. C.S. is funded by CRUK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, the Butterfield and Stoneygate Trusts, the Novo Nordisk Foundation (ID16584), the Royal Society Professorship Enhancement Award (RP/EA/180007), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the CRUK-University College London Centre, the Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (BCRF 20-157). This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (SU2C-AACR-DT23-17 to S.M.D. and A.E.S.). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 835297). P.V.L. and J.D. are supported by the Francis Crick Institute, which receives its core funding from CRUK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202). For the purpose of open access, the authors have applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. P.V.L. and J.D. are also supported by the Medical Research Council (MR/L016311/1). J.D. is supported by the European Union’s Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant agreement no. 703594-DECODE) and the Research Foundation–Flanders (FWO, grant no. 12J6916N). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support for the establishment of The Francis Crick Institute. P.V.L. is a CPRIT Scholar in Cancer Research and acknowledges CPRIT grant support (RR210006). W.W. is supported by the Human Cell Atlas Seed Network-Retina by the Chan Zuckerberg Institute and NIH R01CA183793, R01CA239342, R01CA158113, P30CA016672 and P50CA221707. This study makes use of data generated by TRACERx Consortium and provided by the UCL Cancer Institute and The Francis Crick Institute. The TRACERx study is sponsored by University College London, funded by CRUK and coordinated through CRUK and the UCL Cancer Trials Centre. This study makes use of data generated by METABRIC and provided by CRUK and the British Columbia Cancer Agency Branch. The METABRIC study is funded by CRUK, the British Columbia Cancer Foundation and the Canadian Breast Cancer Foundation BC/Yukon. Funding Information: A.M. receives royalties for a pancreatic cancer biomarker test from Cosmos Wisdom Biotechnology. A.M. is also listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection. A.M. is a consultant for Freenome and Tezcat Biotechnology. J.Z. reports research funding from Merck and Johnson & Johnson and consultant fees from Bristol Myers Squibb (BMS), Johnson & Johnson, AstraZeneca, Geneplus, OrigMed and Innovent outside of 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 and Gateway for Cancer Research. W.W. reports research funding from Curis, Inc. J.P.S. and W.W. report research funding from Celsius Therapeutics. J.P.S. is a paid consultant for Engine Biosciences. S.K. has ownership interest in MolecularMatch, Lutris and Iylon and is a consultant for Genentech, EMD Serono, Merck, Holy Stone, Novartis, Eli Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, Abbvie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotechnology, Bicara Therapeutics, Endeavor BioMedicines, Numab Pharma and Johnson & Johnson/Janssen and receive research funding from Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Eli Lilly and Daiichi Sankyo. P.A.F. reports research funding from MEI Pharma, Inc. P.H.B. owns stock in GeneTex. C.S. acknowledges grant support from AstraZeneca, Boehringer Ingelheim, BMS, Pfizer, Roche-Ventana, Invitae (previously Archer Dx—collaboration in minimal residual disease sequencing technologies) and Ono Pharmaceutical. C.S. is an AstraZeneca Advisory Board member and Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is also chief investigator of the NHS Galleri trial. C.S. has consulted for Amgen, AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, Merck, BMS, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Metabomed, Bicycle Therapeutics, Roche Innovation Centre Shanghai and the Sarah Cannon Research Institute. C.S. had stock options in Apogen Biotechnologies and GRAIL until June 2021; currently has stock options in Epic Bioscience and Bicycle Therapeutics; and has stock options in and is a co-founder of Achilles Therapeutics. C.S. holds various patents relating to assay technology for cancer; US patents relating to detecting tumor mutations and methods for lung cancer detection; and both a European and a US patent related to identifying insertion/deletion mutation targets. All is outside the submitted work. The remaining authors declare no competing interests. Publisher Copyright: © 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.
AB - Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.
U2 - 10.1038/s41587-022-01342-x
DO - 10.1038/s41587-022-01342-x
M3 - Article
AN - SCOPUS:85131877909
SN - 1087-0156
VL - 40
SP - 1624
EP - 1633
JO - Nature Biotechnology
JF - Nature Biotechnology
IS - 11
ER -