Genome Biology (Nov 2020)
Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity
- Won-Chul Lee,
- Alexandre Reuben,
- Xin Hu,
- Nicholas McGranahan,
- Runzhe Chen,
- Ali Jalali,
- Marcelo V. Negrao,
- Shawna M. Hubert,
- Chad Tang,
- Chia-Chin Wu,
- Anthony San Lucas,
- Whijae Roh,
- Kenichi Suda,
- Jihye Kim,
- Aik-Choon Tan,
- David H. Peng,
- Wei Lu,
- Ximing Tang,
- Chi-Wan Chow,
- Junya Fujimoto,
- Carmen Behrens,
- Neda Kalhor,
- Kazutaka Fukumura,
- Marcus Coyle,
- Rebecca Thornton,
- Curtis Gumbs,
- Jun Li,
- Chang-Jiun Wu,
- Latasha Little,
- Emily Roarty,
- Xingzhi Song,
- J. Jack Lee,
- Erik P. Sulman,
- Ganesh Rao,
- Stephen Swisher,
- Lixia Diao,
- Jing Wang,
- John V. Heymach,
- Jason T. Huse,
- Paul Scheet,
- Ignacio I. Wistuba,
- Don L. Gibbons,
- P. Andrew Futreal,
- Jianhua Zhang,
- Daniel Gomez,
- Jianjun Zhang
Affiliations
- Won-Chul Lee
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Alexandre Reuben
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center
- Xin Hu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Nicholas McGranahan
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Runzhe Chen
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Ali Jalali
- Department of Neurosurgery, Baylor College of Medicine
- Marcelo V. Negrao
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center
- Shawna M. Hubert
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Chad Tang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center
- Chia-Chin Wu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Anthony San Lucas
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center
- Whijae Roh
- Broad Institute of Harvard and Massachusetts Institute of Technology
- Kenichi Suda
- Department of Thoracic Surgery, Kindai University Faculty of Medicine
- Jihye Kim
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus
- Aik-Choon Tan
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center
- David H. Peng
- NYU Langone Health
- Wei Lu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center
- Ximing Tang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center
- Chi-Wan Chow
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center
- Junya Fujimoto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center
- Carmen Behrens
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center
- Neda Kalhor
- Department of Pathology, The University of Texas MD Anderson Cancer Center
- Kazutaka Fukumura
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center
- Marcus Coyle
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Rebecca Thornton
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Curtis Gumbs
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Jun Li
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Chang-Jiun Wu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Latasha Little
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Emily Roarty
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center
- Xingzhi Song
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- J. Jack Lee
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center
- Erik P. Sulman
- New York University Langone School of Medicine
- Ganesh Rao
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center
- Stephen Swisher
- Department of Thoracic Surgery, The University of Texas MD Anderson Cancer Center
- Lixia Diao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
- Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
- John V. Heymach
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center
- Jason T. Huse
- Department of Pathology, The University of Texas MD Anderson Cancer Center
- Paul Scheet
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center
- Ignacio I. Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center
- Don L. Gibbons
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center
- P. Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Daniel Gomez
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center
- Jianjun Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- DOI
- https://doi.org/10.1186/s13059-020-02175-0
- Journal volume & issue
-
Vol. 21,
no. 1
pp. 1 – 21
Abstract
Abstract Background Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. Results We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. Conclusions Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.
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