Timing and Origins of Local and Distant Metastases in Lung Cancer

作者：Wen‐Fang Tang, Min Wu, Hua Bao, Yang Xu, Jieshan Lin, Yi Liang, Yu Zhang, Xiangpeng Chu, Zhen‐Bin Qiu, Jian Su, Jia‐Tao Zhang, Chao Zhang, Fangping Xu, Jinghua Chen, Rui Fu, Ying Chen, Tao Yang, Qing-Ke Chen, Tingting Wu, Xue Wu, Yang Shao, Jiantao Zheng, Zhi Xie, Zhiyi Lv, Song Dong, Yi‐Long Wu, Wen‐Zhao Zhong · 发表于：Journal of Thoracic Oncology · 年份：2021 · DOI：10.1016/j.jtho.2021.02.023 · 被引用次数：94 · 研究领域：Cancer Genomics and Diagnostics、Lung Cancer Treatments and Mutations、Lung Cancer Diagnosis and Treatment

INTRODUCTION: Metastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive. METHODS: We performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models. RESULTS: There were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph node metastases whose dissemination time was relatively early. By analyzing the evolutionary origins, we reported that nonlymph node metastases were mainly seeded by the PT (87.5%) rather than ...