Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression

Shaolong Cao; Jennifer R Wang; Shuangxi Ji; Peng Yang; Yaoyi Dai; Shuai Guo; Matthew D Montierth; John Paul Shen; Xiao Zhao; Jingxiao Chen; Jaewon James Lee; Paola A Guerrero; Nicholas Spetsieris; Nikolai Engedal; Sinja Taavitsainen; Kaixian Yu; Julie Livingstone; Vinayak Bhandari; Shawna M Hubert; Najat C Daw; P Andrew Futreal; Eleni Efstathiou; Bora Lim; Andrea Viale; Jianjun Zhang; Matti Nykter; Bogdan A Czerniak; Powel H Brown; Charles Swanton; Pavlos Msaouel; Anirban Maitra; Scott Kopetz; Peter Campbell; Terence P Speed; Paul C Boutros; Hongtu Zhu; Alfonso Urbanucci; Jonas Demeulemeester; Peter Van Loo; Wenyi Wang

doi:10.1038/s41587-022-01342-x

Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression

Nat Biotechnol. 2022 Nov;40(11):1624-1633. doi: 10.1038/s41587-022-01342-x. Epub 2022 Jun 13.

Authors

Shaolong Cao^#¹, Jennifer R Wang^#², Shuangxi Ji^#¹, Peng Yang^{1

3}, Yaoyi Dai^{1

4}, Shuai Guo¹, Matthew D Montierth^{1

4}, John Paul Shen⁵, Xiao Zhao², Jingxiao Chen¹, Jaewon James Lee^{6

7

8}, Paola A Guerrero^{6

7}, Nicholas Spetsieris⁹, Nikolai Engedal¹⁰, Sinja Taavitsainen¹¹, Kaixian Yu¹², Julie Livingstone^{13

14

15

16}, Vinayak Bhandari¹⁷, Shawna M Hubert¹⁸, Najat C Daw¹⁹, P Andrew Futreal²⁰, Eleni Efstathiou⁹, Bora Lim²¹, Andrea Viale²⁰, Jianjun Zhang¹⁸, Matti Nykter¹¹, Bogdan A Czerniak²², Powel H Brown²³, Charles Swanton²⁴, Pavlos Msaouel^{7

9}, Anirban Maitra^{6

7

22}, Scott Kopetz⁵, Peter Campbell²⁵, Terence P Speed^{26

27}, Paul C Boutros^{13

14

15

16

17}, Hongtu Zhu¹², Alfonso Urbanucci¹⁰, Jonas Demeulemeester^{28

29}, Peter Van Loo^{28

30}, Wenyi Wang^{31

32}

Affiliations

¹ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Statistics, Rice University, Houston, TX, USA.
⁴ Baylor College of Medicine, Houston, TX, USA.
⁵ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
¹¹ Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere, Finland.
¹² Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁵ Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁶ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁷ Department of Medical Biophysics, University of Toronto, Toronto ON, Canada.
¹⁸ Department of Thoracic Head Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁹ Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁰ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²¹ Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²² Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²³ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁴ The Francis Crick Institute, London, UK.
²⁵ Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
²⁶ Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VC, Australia.
²⁷ School of Mathematics and Statistics, The University of Melbourne, Melbourne, VC, Australia.
²⁸ Cancer Genomics Laboratory, The Francis Crick Institute, London, UK.
²⁹ Department of Human Genetics, KU Leuven, Leuven, Belgium.
³⁰ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³¹ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. wwang7@mdanderson.org.
³² Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. wwang7@mdanderson.org.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Disease Progression
Genetic Heterogeneity
Genomics
Humans
Neoplasms* / genetics
Neoplasms* / metabolism
RNA, Messenger / genetics

Substances

RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding