Lee Won-Chul, Reuben Alexandre, Hu Xin, McGranahan Nicholas, Chen Runzhe, Jalali Ali, Negrao Marcelo V, Hubert Shawna M, Tang Chad, Wu Chia-Chin, Lucas Anthony San, Roh Whijae, Suda Kenichi, Kim Jihye, Tan Aik-Choon, Peng David H, Lu Wei, Tang Ximing, Chow Chi-Wan, Fujimoto Junya, Behrens Carmen, Kalhor Neda, Fukumura Kazutaka, Coyle Marcus, Thornton Rebecca, Gumbs Curtis, Li Jun, Wu Chang-Jiun, Little Latasha, Roarty Emily, Song Xingzhi, Lee J Jack, Sulman Erik P, Rao Ganesh, Swisher Stephen, Diao Lixia, Wang Jing, Heymach John V, Huse Jason T, Scheet Paul, Wistuba Ignacio I, Gibbons Don L, Futreal P Andrew, Zhang Jianhua, Gomez Daniel, Zhang Jianjun
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Genome Biol. 2020 Nov 4;21(1):271. doi: 10.1186/s13059-020-02175-0.
Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary.
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.
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.
转移是癌症死亡的主要原因，占癌症死亡人数的90%。我们对驱动转移的分子机制的了解还很初步。
我们对8对非小细胞肺癌（NSCLC）原发肿瘤和配对的远处转移灶进行了全外显子组测序（WES）、RNA测序、甲基化微阵列和免疫组织化学（IHC）。此外，我们分析了来自35对原发性NSCLC和转移灶的已发表WES数据，以及来自4例转移性NSCLC尸检病例和一个转移性肺癌小鼠模型的转录组数据。虽然突变特征表明转移扩散前后存在不同的诱变过程，但大多数体细胞突变在原发性肿瘤和配对的远处转移灶之间是共享的。亚克隆分析显示42例患者中有41例存在单克隆播种的证据。转录组数据的通路分析表明，转移灶中下调的通路主要与免疫相关。进一步的反卷积分析显示，除CD4+T细胞和M2巨噬细胞外，转移灶中各种免疫细胞类型的浸润显著降低。这些结果与免疫组化显示的转移灶中免疫细胞密度较低和CD4/CD8比值较高一致。对尸检病例和动物模型的转录组数据的分析证实，颅外转移灶中也存在免疫抑制。转移灶中体细胞拷贝数畸变和等位基因不平衡负担显著更高。
转移是一个分子层面的晚期事件，由包括体细胞拷贝数畸变在内的不同分子事件驱动的免疫抑制可能是具有转移可塑性的肿瘤的共同特征。
