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Multi-regional sequencing reveals clonal and polyclonal seeding from primary tumor to metastases in advanced gastric cancer

多区域测序揭示晚期胃癌从原发肿瘤到转移的克隆和多克隆种植

  • 影响因子:4.73
  • DOI:10.1007/s00535-019-01659-6
  • 作者列表:"Hirotsu, Yosuke","Hada, Masao","Amemiya, Kenji","Oyama, Toshio","Mochizuki, Hitoshi","Omata, Masao
  • 发表时间:2020-01-07
Abstract

Background Tumor metastases to lymph nodes and distant organs are associated with worse prognosis in gastric cancer. However, little is known about the genetic profiles, subclonal architecture, and evolutional processes across primary tumors and metastases. Methods We analyzed the genetic alterations of 106 multiregional samples including primary tumors, lymph node metastases, and visceral metastases from 10 patients with advanced gastric cancer. Histologically different portions were obtained by laser-capture microdissection. We reconstructed the subclonal architectures and inferred the primary to lymph or visceral metastatic seeding patterns. Results The different histological portions in primary tumors had common mutations, suggesting common ancestral tumor origins transformed into distinct histological types. In almost all cases, TP53 mutations were identified as clonal mutations across primary tumors and metastases. Subclonal reconstruction and phylogenetic analysis showed primary tumors were classified into monoclonal or polyclonal tumors. All monoclonal primary tumors disseminated as metastases with the same tumor composition (100%, 26/26 samples). In contrast, polyclonal primary tumors mainly spread as metastases by way of polyclonal seeding (84%: 37/44 samples). Conclusions Clonal mutations were maintained at both the primary and metastatic sites and genetic divergence of these was low. These findings shed light on the genetic basis of primary tumor dissemination and metastatic processes in advanced gastric cancer.

摘要

背景: 胃癌淋巴结和远处器官的肿瘤转移与较差的预后相关。然而,关于原发肿瘤和转移灶的遗传谱、亚克隆结构和进化过程知之甚少。方法我们分析了 10 例晚期胃癌患者 106 例多区域样本的遗传学改变,包括原发肿瘤、淋巴结转移和内脏转移。通过激光捕获显微切割获得组织学不同的部分。我们重建了亚克隆架构,并推断了原发至淋巴或内脏转移的种植模式。结果原发肿瘤不同组织学部位有共同的突变,提示共同的祖先肿瘤起源转化为不同的组织学类型。在几乎所有的病例中,TP53 突变被鉴定为跨原发肿瘤和转移灶的克隆性突变。亚克隆重建和系统发育分析显示原发肿瘤分为单克隆或多克隆肿瘤。所有单克隆原发肿瘤均播散为转移灶,肿瘤成分相同 (100%,26/26 例样本)。相比之下,多克隆原发肿瘤主要通过多克隆种植 (84%: 37/44 个样本) 以转移方式扩散。结论克隆性突变在原发和转移部位均保持不变,且遗传差异较低。这些发现揭示了晚期胃癌原发肿瘤播散和转移过程的遗传基础。

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