@article{3a8007974813462b848efdcab8635c70,
title = "Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity",
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.",
keywords = "DNA methylation, Gene expression, Genomics, Immune profiling, Lung cancer, Metastasis, Multiomics",
author = "Lee, {Won Chul} and Alexandre Reuben and Xin Hu and Nicholas McGranahan and Runzhe Chen and Ali Jalali and Negrao, {Marcelo V.} and Hubert, {Shawna M.} and Chad Tang and Wu, {Chia Chin} and Lucas, {Anthony San} and Whijae Roh and Kenichi Suda and Jihye Kim and Tan, {Aik Choon} and Peng, {David H.} and Wei Lu and Ximing Tang and Chow, {Chi Wan} and Junya Fujimoto and Carmen Behrens and Neda Kalhor and Kazutaka Fukumura and Marcus Coyle and Rebecca Thornton and Curtis Gumbs and Jun Li and Wu, {Chang Jiun} and Latasha Little and Emily Roarty and Xingzhi Song and Lee, {J. Jack} and Sulman, {Erik P.} and Ganesh Rao and Stephen Swisher and Lixia Diao and Jing Wang and Heymach, {John V.} and Huse, {Jason T.} and Paul Scheet and Wistuba, {Ignacio I.} and Gibbons, {Don L.} and Futreal, {P. Andrew} and Jianhua Zhang and Daniel Gomez and Jianjun Zhang",
note = "Funding Information: We acknowledge Institutional Tissue Bank that provided samples for this project. This facility is funded by NCI # CA16672. The review history is available as Additional?file?3. Anahita Bishop was the primary editor of this article and managed its editorial process and peer review in collaboration with the rest of the editorial team. Funding Information: We acknowledge Institutional Tissue Bank that provided samples for this project. This facility is funded by NCI # CA16672. Funding Information: JZ reports research funding from Merck and Johnson & Johnson and personal fees from AstraZeneca, Bristol-Myers Squibb, Johnson & Johnson GenePlus-Beijing Institute, OrigiMed, and Innovent outside the submitted work. KS reports research funding from Boehringer Ingelheim and Rain Therapeutics, and personal fees from AstraZeneca and Boehringer Ingelheim (all outside the submitted work). DLG has served on the scientific advisory committees for AstraZeneca, GlaxoSmithKline, Sanofi, and Janssen and has received research support from Janssen, Takeda, Ribon Therapeutics, Astellas, and AstraZeneca. Funding Information: This work is supported by the generous philanthropic contributions to the University of Texas MD Anderson Cancer Center Lung Moon Shot Program, Cancer Prevention and Research Institute of Texas Multi-Investigator Research Award grant (RP160668), MD Anderson Physician Scientist Award, TJ Martell Foundation, the Conquer Cancer Foundation, and the Lung Cancer Research Foundation. Acknowledgements Review history Peer review information Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1186/s13059-020-02175-0",
language = "English (US)",
volume = "21",
journal = "Genome biology",
issn = "1474-7596",
publisher = "BioMed Central",
number = "1",
}