Year-end Sale % OFF 
Abstract
BackgroundMetastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary.ResultsWe 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.ConclusionsMetastasis 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.
Highlights
Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths
Metastasis is a molecularly late event following the clonal expansion model We first investigated the difference of somatic mutations between primary tumors and matched distant metastases in the 7 patients with available paired germline DNA
Despite a wide span (3 to 24 months, a median of 9 months) and different therapies between resection of primary tumors and metastases (Additional file 1: Table S2), an average of 67% of mutations were shared between primary tumors and matched distant metastases (Fig. 1) and the tumor mutation burden (TMB) was similar between primary non-small cell lung cancer (NSCLC) tumors and metastases (Additional file 2: Fig. S1A)
Summary
Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Comparative studies on paired primary tumors and metastases have the potential to identify molecular changes associated with the development of metastasis. Using this approach, several studies have revealed a varying degree of genetic divergence between primary tumors and metastases [7,8,9,10,11]. We reanalyzed previously published WES data from 35 pairs of primary NSCLC tumors and matched brain metastases (Brastianos cohort) [11] and RNA-seq data from 4 patients with extensive metastatic NSCLC [16] and from a metastatic lung cancer mouse model [17] and compared these results to intratumor heterogeneity (ITH) data in primary NSCLC tumors from the TRACERx dataset [18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
