Genetic and clonal dissection of osteosarcoma progression and lung metastasis
Genetic and clonal dissection of osteosarcoma progression and lung metastasis
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DOI：
10.1002/ijc.31389
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发表时间：
2018-09-01
影响因子：
6.4
通讯作者：
Wang, Jin
中科院分区：
文献类型：
--
作者：
Xu, Huaiyuan;Zhu, Xiaojun;Wang, Jin
骨肉瘤是一种原发性恶性骨肿瘤，有很高的可能转移到肺部。关于OS癌细胞向肺部扩散的潜在机制知之甚少。我们对13例OS原发性肿瘤进行了全外显子组测序，并对肺转移瘤和正常组织进行了匹配。系统发育分析显示，肺转移性肿瘤常常具有在匹配的原发性OS肿瘤中不存在或罕见的克隆。空间和时间上分离的肺转移来自多系模式的平行接种事件。TP 53或RB 1的丢失是OS肿瘤发生期间的早期事件之一，而PTEN的丢失涉及与肺转移相关的后期阶段。最后，KEAP 1被确定为增加转移风险的新生物标志物。原发性肿瘤携带KEAP 1扩增的患者的无肺转移生存率明显较差。这一发现在两个独立的数据集中得到了验证。此外，体外实验显示KEAP 1缺失抑制OS细胞的侵袭。我们的研究结果揭示了OS进展过程中的克隆进化模式，并强调KEAP 1是与OS患者肺转移风险相关的新候选基因。骨肉瘤中癌细胞向肺部的扩散很难控制，并可能导致疾病的进一步进展。然而，关于骨肉瘤肺转移的机制知之甚少。在这里，全面的全外显子组测序比较原发性和转移性骨肉瘤之间的遗传改变表明，转移性肿瘤的港口克隆是独特的，从那些原发性肿瘤。确定了与肿瘤进展相关的特定遗传事件。特别是，KEAP 1扩增与肺无转移生存率显著降低相关，使其成为骨肉瘤患者转移风险增加的潜在有价值的生物标志物。
Osteosarcoma is a primary malignant bone tumor that has a high potential to metastasize to lungs. Little is known about the mechanisms underlying the dissemination of OS cancer cells to lungs. We performed whole exome sequencing of 13 OS primary tumors, with matched lung metastases and normal tissues. Phylogenetic analyses revealed that lung metastatic tumors often harbor clones that are nonexistent or rare in the matched primary OS tumors. Spatially and temporally separated lung metastases were from parallel seeding events with a polyphyletic pattern. Loss of TP53 or RB1 is among the early events during OS tumorigenesis, while loss of PTEN is involved at the later stages associated with lung metastases. Finally, KEAP1 was identified as a novel biomarker for increased metastatic risk. Patients whose primary tumors harbored KEAP1 amplification have significantly poorer lung-metastasis free survival. This finding was validated in two independent datasets. Further, in vitro experiments exhibited that KEAP1 depletion suppressed the invasion of OS cells. Our findings uncover the patterns of clonal evolution during OS progression and highlight KEAP1 as a novel candidate associated with the risk of lung metastasis in OS patients.What's new? The spread of cancer cells to the lungs in osteosarcoma is difficult to control and can fuel further progression of the disease. Little is known, however, about the mechanisms behind lung metastasis in osteosarcoma. Here, comprehensive whole exome sequencing comparing genetic alterations between primary and metastatic osteosarcomas shows that metastatic tumors harbor clones that are unique from those of primary tumors. Specific genetic events were identified in association with tumor progression. In particular, KEAP1 amplification was associated with significantly worse lung metastasis-free survival, making it a potentially valuable biomarker for increased metastatic risk in osteosarcoma patients.