Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

被引：43

作者：

Lee, Won-Chul ^{[1
,2
]}

Reuben, Alexandre ^{[2
]}

Hu, Xin ^{[1
,2
]}

McGranahan, Nicholas ^{[3
]}

Chen, Runzhe ^{[1
,2
]}

Jalali, Ali ^{[4
]}

Negrao, Marcelo, V ^{[2
]}

Hubert, Shawna M. ^{[1
,2
]}

Tang, Chad ^{[5
]}

Wu, Chia-Chin ^{[1
]}

San Lucas, Anthony ^{[6
]}

Roh, Whijae ^{[7
,8
]}

Suda, Kenichi ^{[9
]}

Kim, Jihye ^{[10
]}

Tan, Aik-Choon ^{[11
]}

Peng, David H. ^{[12
]}

Lu, Wei ^{[13
]}

Tang, Ximing ^{[13
]}

Chow, Chi-Wan ^{[13
]}

Fujimoto, Junya ^{[13
]}

Behrens, Carmen ^{[2
]}

Kalhor, Neda ^{[14
]}

Fukumura, Kazutaka ^{[13
]}

Coyle, Marcus ^{[1
]}

Thornton, Rebecca ^{[1
]}

Gumbs, Curtis ^{[1
]}

Li, Jun ^{[1
]}

Wu, Chang-Jiun ^{[1
]}

Little, Latasha ^{[1
]}

Roarty, Emily ^{[2
]}

Song, Xingzhi ^{[1
]}

Lee, J. Jack ^{[15
]}

Sulman, Erik P. ^{[16
]}

Rao, Ganesh ^{[17
]}

Swisher, Stephen ^{[18
]}

Diao, Lixia ^{[19
]}

Wang, Jing ^{[19
]}

Heymach, John, V ^{[2
]}

Huse, Jason T. ^{[14
]}

Scheet, Paul ^{[6
]}

Wistuba, Ignacio I. ^{[13
]}

Gibbons, Don L. ^{[2
]}

Futreal, P. Andrew ^{[1
]}

Zhang, Jianhua ^{[1
]}

Gomez, Daniel ^{[5
,20
]}

Zhang, Jianjun ^{[1
,2
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[3] Univ Coll London Canc Inst, Canc Res UK Lung Canc Ctr Excellence, London, England

[4] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX USA

[7] Broad Inst Harvard, Cambridge, MA USA

[8] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[9] Kindai Univ, Dept Thorac Surg, Fac Med, Osakasayama, Japan

[10] Univ Colorado, Div Med Oncol, Anschutz Med Campus, Aurora, CO USA

[11] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA

[12] NYU, Langone Hlth, New York, NY USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA

[15] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA

[16] NYU, Langone Sch Med, New York, NY USA

[17] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX USA

[18] Univ Texas MD Anderson Canc Ctr, Dept Thorac Surg, Houston, TX USA

[19] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX USA

[20] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA

来源：

GENOME BIOLOGY | 2020年 / 21卷 / 01期

关键词：

Lung cancer; Metastasis; Multiomics; Immune profiling; Genomics; DNA  methylation; Gene expression; SUBTLE ALLELIC IMBALANCE; BRAIN METASTASES; MUTATIONAL PROCESSES; COPY NUMBER; HETEROGENEITY; EVOLUTION; SIGNATURES; MICROENVIRONMENT; ASSOCIATION; REPERTOIRE;

D O I：

10.1186/s13059-020-02175-0

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：21

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