Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy.
Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy.
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通过新辅助化疗跟踪食管腺癌的基因组进化。
DOI：
10.1158/2159-8290.cd-15-0412
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发表时间：
2015-08
期刊：
影响因子：
28.2
通讯作者：
Swanton C
中科院分区：
文献类型：
--
作者：
Murugaesu N;Wilson GA;Birkbak NJ;Watkins T;McGranahan N;Kumar S;Abbassi-Ghadi N;Salm M;Mitter R;Horswell S;Rowan A;Phillimore B;Biggs J;Begum S;Matthews N;Hochhauser D;Hanna GB;Swanton C
食管腺癌（EACs）与预后差有关。破译这种疾病的进化历史可能会揭示治疗上可处理的靶点，并揭示疾病过程中和新辅助化疗（NAC）后的动态突变过程。我们对8例可手术的EACs患者在含铂NAC前后的40个肿瘤区域进行了外显子组测序。这揭示了EACs的进化基因组景观，存在异质驱动突变、平行进化、早期基因组加倍事件以及肿瘤内高异质性与NAC反应差之间的关联。在比较早期和晚期突变过程时，多区域测序显示CTT背景下T>G突变显著减少，并且在NAC后CpC背景下存在富集C> a突变的铂标记。EACs的特点是早期染色体不稳定，导致扩增含有可靶向的癌基因，通过化疗持续存在，为未来的治疗方法提供了基本原理。
Esophageal adenocarcinomas (EACs) are associated with dismal prognosis. Deciphering the evolutionary histories of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable EACs, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of EACs with the presence of heterogeneous driver mutations, parallel evolution, early genome doubling events and an association between high intratumor heterogeneity and poor response to NAC. Multi-region sequencing demonstrated a significant reduction in T>G mutations within a CTT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of C>A mutations within a CpC context following NAC. EACs are characterized by early chromosomal instability leading to amplifications containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches.