Multiregion Sequencing Reveals the Genetic Heterogeneity and Evolutionary History of Osteosarcoma and Matched Pulmonary Metastases
Multiregion Sequencing Reveals the Genetic Heterogeneity and Evolutionary History of Osteosarcoma and Matched Pulmonary Metastases
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多区域测序揭示骨肉瘤和匹配肺转移瘤的遗传异质性和进化史
DOI：
10.1158/0008-5472.can-18-1086
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发表时间：
2019-01-01
期刊：
影响因子：
11.2
通讯作者：
Wang, Jie
中科院分区：
文献类型：
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作者：
Wang, Di;Niu, Xiaohui;Wang, Jie
骨肉瘤是最常见的原发性骨恶性肿瘤，肺是最常见的转移部位。对肺转移性骨肉瘤的肿瘤异质性和基因组改变的进化过程的有限理解阻碍了新的治疗策略的发展。在这里，我们系统地说明原发性肿瘤和相应的肺转移性肿瘤之间的基因组差异，多区域全外显子组和全基因组测序在86个肿瘤区域从10例骨肉瘤患者。与原发性肿瘤相比，转移性肿瘤表现出显著更高的突变负荷和基因组不稳定性，这可能是由于转移性肿瘤中DNA损伤反应基因的大量改变引起的突变积累。综合分析亚克隆的结构和相互关系，发现骨肉瘤在肺转移过程中存在动态的突变过程和多样化的播散模式（6/10为线性模式，4/10为平行演变模式）。所有患者的原发性肿瘤和转移性肿瘤之间均表现出更显著的肿瘤间异质性，而不是肿瘤内异质性。在肿瘤演变的早期和晚期阶段，突变基因在PI 3 K-Akt通路中富集，并且在转移阶段在MAPK通路中富集。相反，转移性肿瘤显示出改善的免疫原性，包括比相应的原发性肿瘤更高的新抗原载量、升高的PD-L1表达和肿瘤浸润淋巴细胞。本研究首次报道了骨肉瘤肺转移的动态演变过程和肿瘤的时空异质性，为骨肉瘤肺转移的诊断和潜在的治疗策略提供了新的见解。意义：原发性和转移性骨肉瘤的高通量测序为骨肉瘤肺转移的诊断和潜在的临床治疗策略提供了新的见解。
Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolution ary patterns). All patients demonstrated more significant inter-tumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis.Significance: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.