A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy
A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy
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DOI：
10.1101/gr.214296.116
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发表时间：
2017-06-01
期刊：
影响因子：
7
通讯作者：
Fitzgerald, Rebecca C.
中科院分区：
文献类型：
--
作者：
Noorani, Ayesha;Bornschein, Jan;Fitzgerald, Rebecca C.
科学界避免使用接受过全身化疗的患者的组织样本来推断特定癌症的基因组格局。食管腺癌是一种异质性、化疗耐药的肿瘤，其治疗前内镜样本的可用性和大小是有限的。本研究比较了从化疗初治和化疗处理的样品中获得的全基因组测序数据。无论化疗状态如何，所有样本的全基因组测序数据的质量都相当。纳入化疗后收集的样本增加了晚期肿瘤的比例。当比较来自10个病例的匹配的化疗前和化疗后样本时，突变特征、拷贝数和SNV突变谱反映了这种疾病的预期异质性。与等位基因特异性拷贝数变化相关的SNV分析将共同祖先精确定位到化疗前的某个点。对于化疗前和化疗后样本确实显示出实质性差异的情况，分歧的时间与核内复制接近同步。在一个大型前瞻性队列（62个未经治疗的样本，58个化疗治疗的样本）中进行比较，发现在化疗状态方面，总体突变率、突变特征、特定复发点突变或拷贝数事件无显著差异。总之，新辅助化疗后获得的样本的全基因组测序是食管腺癌基因组景观的代表。排除这些样本减少了可用于编目的材料，并引入了对癌症早期阶段的偏见。
The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.