Tao Jiang1, Zhaoyuan Fang2, Shijie Tang2, Ruirui Cheng3, Yanan Li4, Shengxiang Ren1, Chunxia Su1, Weijie Min4, Xianchao Guo5, Wei Zhu5, Henghui Zhang5, Likun Hou6, Yuanwei Pan7, Zhigang Zhou7, Jun Zhang8, Guojun Zhang3, Zhijian Yue4, Luonan Chen9, Caicun Zhou10. 1. Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, People's Republic of China. 2. State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China. 3. Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China. 4. Department of Neurosurgery, Changhai Hospital Affiliated to Second Military Medical University, Shanghai, People's Republic of China. 5. Beijing Genecast Biotechnology Co., Beijing, People's Republic of China. 6. Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. 7. Department of Imaging and Nuclear Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China. 8. Division of Medical Oncology, Department of Internal Medicine, University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Missouri; Department of Cancer Biology, University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Missouri. 9. Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China. 10. Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, People's Republic of China. Electronic address: caicunzhou_dr@163.com.
Abstract
INTRODUCTION: A comprehensive genomic analysis of paired primary tumors and their metastatic lesions may provide new insights into the biology of metastatic processes and therefore guide the development of novel strategies for intervention. To date, our knowledge of the genetic divergence and phylogenetic relationships among diverse metastatic lesions from cancer remains limited. METHODS: We performed whole-exome sequencing in 84 tissue and blood samples from 26 patients with lung adenocarcinoma having liver metastases (LiM) or brain metastases (BrM) before any systemic therapy, with the goal to molecularly characterize the metastatic process. Mutational landscape and evolutionary patterns were compared between paired primary lesions (primary lesion of LiM or BrM) and metastases (metastatic site of LiM or BrM). RESULTS: We found that common driver mutations, including TP53 and EGFR, were highly consistent between paired primary and metastatic tumors. Although tumor mutational burden was comparable among groups, the LiM group had significantly higher mutational and copy number variational similarity than the BrM group between paired primary lesions and metastases (p = 0.019 and p = 0.035, respectively). Phylogenetic analysis further revealed that LiM-competent disseminations had a higher level of genetic similarity to their paired primary lesions and were genetically diverged from their primary tumors at a relatively later stage than those of BrM. These results suggest that LiM favorably followed the linear progression model, whereas BrM was more consistent with the parallel progression model. CONCLUSIONS: This study suggests that the mutational landscape and evolutionary pattern was distinctly different between the LiM and BrM of lung adenocarcinoma.
INTRODUCTION: A comprehensive genomic analysis of paired primary tumors and their metastatic lesions may provide new insights into the biology of metastatic processes and therefore guide the development of novel strategies for intervention. To date, our knowledge of the genetic divergence and phylogenetic relationships among diverse metastatic lesions from cancer remains limited. METHODS: We performed whole-exome sequencing in 84 tissue and blood samples from 26 patients with lung adenocarcinoma having liver metastases (LiM) or brain metastases (BrM) before any systemic therapy, with the goal to molecularly characterize the metastatic process. Mutational landscape and evolutionary patterns were compared between paired primary lesions (primary lesion of LiM or BrM) and metastases (metastatic site of LiM or BrM). RESULTS: We found that common driver mutations, including TP53 and EGFR, were highly consistent between paired primary and metastatic tumors. Although tumor mutational burden was comparable among groups, the LiM group had significantly higher mutational and copy number variational similarity than the BrM group between paired primary lesions and metastases (p = 0.019 and p = 0.035, respectively). Phylogenetic analysis further revealed that LiM-competent disseminations had a higher level of genetic similarity to their paired primary lesions and were genetically diverged from their primary tumors at a relatively later stage than those of BrM. These results suggest that LiM favorably followed the linear progression model, whereas BrM was more consistent with the parallel progression model. CONCLUSIONS: This study suggests that the mutational landscape and evolutionary pattern was distinctly different between the LiM and BrM of lung adenocarcinoma.
Authors: Bethany K Campbell; Zijie Gao; Niall M Corcoran; Stanley S Stylli; Christopher M Hovens Journal: Cancers (Basel) Date: 2022-10-10 Impact factor: 6.575