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Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma
Journal of Hepatology ( IF 25.7 ) Pub Date : 2018-07-01 , DOI: 10.1016/j.jhep.2018.02.029 Liang-Qing Dong , Yang Shi , Li-Jie Ma , Liu-Xiao Yang , Xiao-Ying Wang , Shu Zhang , Zhi-Chao Wang , Meng Duan , Zhao Zhang , Long-Zi Liu , Bo-Hao Zheng , Zhen-Bin Ding , Ai-Wu Ke , Da-Ming Gao , Ke Yuan , Jian Zhou , Jia Fan , Ruibin Xi , Qiang Gao
Journal of Hepatology ( IF 25.7 ) Pub Date : 2018-07-01 , DOI: 10.1016/j.jhep.2018.02.029 Liang-Qing Dong , Yang Shi , Li-Jie Ma , Liu-Xiao Yang , Xiao-Ying Wang , Shu Zhang , Zhi-Chao Wang , Meng Duan , Zhao Zhang , Long-Zi Liu , Bo-Hao Zheng , Zhen-Bin Ding , Ai-Wu Ke , Da-Ming Gao , Ke Yuan , Jian Zhou , Jia Fan , Ruibin Xi , Qiang Gao
BACKGROUND & AIMS
Intrahepatic cholangiocarcinoma (ICC) is the second-most lethal primary liver cancer. Little is known about intratumoral heterogeneity (ITH) and its impact on ICC progression. We aimed to investigate the ITH of ICC in the hope of helping to develop new therapeutic strategies. METHODS
We obtained 69 spatially distinct regions from six operable ICCs. Patient-derived primary cancer cells (PDPCs) were established for each region, followed by whole-exome sequencing (WES) and multi-level validation. RESULTS
We observed widespread ITH for both somatic mutations and clonal architecture, shaped by multiple mechanisms, like clonal "illusion", parallel evolution and chromosome instability. A median of 60.3% of mutations were heterogeneous, among which 85% of the driver mutations were located on the branches of tumor phylogenetic trees. Many truncal and clonal driver mutations occurred in tumor suppressor genes, such as TP53, SMARCB1 and PBRM1 that are involved in DNA repair and chromatin-remodeling. Genome doubling occurred in most cases (5/6) after the accumulation of truncal mutations and was shared by all intratumoral sub-regions. In all cases, ongoing chromosomal instability is evident throughout the evolutionary trajectory of ICC. The recurrence of ICC1239 provided evidence to support the polyclonal metastatic seeding in ICC. The change of mutation landscape and internal diversity among subclones during metastasis, such as the loss of chemoresistance mediator, can be used for new treatment strategies. Targeted therapy against truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, was developed in 5/6 patients. CONCLUSIONS
Integrated investigations of spatial ITH and clonal evolution may provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ICC. LAY SUMMARY
We applied multiregional whole-exome sequencing to investigate the evolution of intrahepatic cholangiocarcinoma (ICC). The results revealed that many factors, such as parallel evolution and chromosome instability, may participate and promote the branch diversity of ICC. Interestingly, in one patient with primary and recurrent metastatic tumors, we found evidence of polyclonal metastatic seeding, indicating that symbiotic communities of multiple clones existed and were maintained during metastasis. More realistically, some truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be promising treatment targets in patients with ICC.
中文翻译:
肝内胆管癌的时空克隆演变
背景和目的 肝内胆管癌 (ICC) 是第二大致死性原发性肝癌。关于瘤内异质性 (ITH) 及其对 ICC 进展的影响知之甚少。我们旨在调查 ICC 的 ITH,希望有助于开发新的治疗策略。方法我们从六个可手术的 ICC 中获得了 69 个空间不同的区域。为每个区域建立患者来源的原代癌细胞 (PDPC),然后进行全外显子组测序 (WES) 和多级验证。结果 我们观察到体细胞突变和克隆结构的广泛 ITH,由多种机制形成,如克隆“错觉”、平行进化和染色体不稳定性。平均 60.3% 的突变是异质的,其中85%的驱动突变位于肿瘤系统发育树的分支上。许多干细胞和克隆驱动突变发生在肿瘤抑制基因中,例如参与 DNA 修复和染色质重塑的 TP53、SMARCB1 和 PBRM1。大多数情况下 (5/6) 发生基因组加倍是在躯干突变积累后,并由所有肿瘤内亚区域共享。在所有情况下,在 ICC 的整个进化轨迹中,持续的染色体不稳定性是显而易见的。ICC1239 的复发提供了支持 ICC 中多克隆转移播种的证据。转移过程中亚克隆之间突变格局和内部多样性的变化,例如化学抗性介质的丢失,可用于新的治疗策略。针对躯干改变的靶向治疗,如 IDH1、JAK1、5/6 患者出现 KRAS 突变和 EGFR 扩增。结论空间 ITH 和克隆进化的综合研究可能为增强对 ICC 肿瘤发生和进展的理解提供重要的分子基础。概述 我们应用多区域全外显子组测序来研究肝内胆管癌 (ICC) 的演变。结果表明,平行进化和染色体不稳定性等多种因素可能参与并促进ICC的分支多样性。有趣的是,在一名患有原发性和复发性转移性肿瘤的患者中,我们发现了多克隆转移性播散的证据,表明多克隆的共生群落存在并在转移过程中得以维持。更现实的是,一些躯干的改变,如 IDH1、JAK1、
更新日期:2018-07-01
中文翻译:
肝内胆管癌的时空克隆演变
背景和目的 肝内胆管癌 (ICC) 是第二大致死性原发性肝癌。关于瘤内异质性 (ITH) 及其对 ICC 进展的影响知之甚少。我们旨在调查 ICC 的 ITH,希望有助于开发新的治疗策略。方法我们从六个可手术的 ICC 中获得了 69 个空间不同的区域。为每个区域建立患者来源的原代癌细胞 (PDPC),然后进行全外显子组测序 (WES) 和多级验证。结果 我们观察到体细胞突变和克隆结构的广泛 ITH,由多种机制形成,如克隆“错觉”、平行进化和染色体不稳定性。平均 60.3% 的突变是异质的,其中85%的驱动突变位于肿瘤系统发育树的分支上。许多干细胞和克隆驱动突变发生在肿瘤抑制基因中,例如参与 DNA 修复和染色质重塑的 TP53、SMARCB1 和 PBRM1。大多数情况下 (5/6) 发生基因组加倍是在躯干突变积累后,并由所有肿瘤内亚区域共享。在所有情况下,在 ICC 的整个进化轨迹中,持续的染色体不稳定性是显而易见的。ICC1239 的复发提供了支持 ICC 中多克隆转移播种的证据。转移过程中亚克隆之间突变格局和内部多样性的变化,例如化学抗性介质的丢失,可用于新的治疗策略。针对躯干改变的靶向治疗,如 IDH1、JAK1、5/6 患者出现 KRAS 突变和 EGFR 扩增。结论空间 ITH 和克隆进化的综合研究可能为增强对 ICC 肿瘤发生和进展的理解提供重要的分子基础。概述 我们应用多区域全外显子组测序来研究肝内胆管癌 (ICC) 的演变。结果表明,平行进化和染色体不稳定性等多种因素可能参与并促进ICC的分支多样性。有趣的是,在一名患有原发性和复发性转移性肿瘤的患者中,我们发现了多克隆转移性播散的证据,表明多克隆的共生群落存在并在转移过程中得以维持。更现实的是,一些躯干的改变,如 IDH1、JAK1、