Comprehensive Analysis for Improvement of the Therapeutic Outcome against Esophageal Cancer by the High-Precision Molecular and Genetic Evaluation

为了获得ESCC基因组改变的全貌，我们对来自日本队列的144对DNA样本进行了全外显子组测序，并结合基于SNP阵列的CN分析。单核苷酸突变的替代模式在病例中差异很大，这种变化不仅与酒精和烟草消费显著相关，而且与相关的遗传因素：ALDH 2和CYP 2A 6多态性显著相关。我们还鉴定了TP 53、NOTCH 1、MLL 2、NFE 2L 2等作为显著突变的基因。此外，TET 2和NFE 2L 2突变分别通过上调侵袭性和氧化还原酶活性而导致恶性肿瘤。最后，我们的通路水平的分析表明，基因组改变分散在癌症相关的通路，包括细胞周期，表观遗传调节因子，NOTCH，RTK-PI 3 K通路等。总的来说，这项研究有助于了解ESCC的病理生理学，并为设计新的治疗策略提供了新的基础。

To obtain a landscape of genomic alterations in ESCC, we performed whole-exome sequencing on 144 paired DNA samples from Japanese cohort, combined with SNP-array based CN profiling. Substitution patterns of single-nucleotide mutations substantially vary among cases, and the variation was significantly associated with not only alcohol and tobacco consumption, but also related genetic factors: ALDH2 and CYP2A6 polymorphisms. We also identified TP53, NOTCH1, MLL2, NFE2L2, etc. as significantly mutated genes. Moreover, TET2 and NFE2L2 mutations contribute to the malignancy by upregulating invasiveness and oxidoreductase activity, respectively. Finally, our pathway-level analysis shows that genomic alteration are dispersed across cancer-associated pathways including cell cycle, epigenetic regulators, NOTCH, RTK-PI3K pathways etc. Collectively, this study contributes to understanding of ESCC pathophysiology and provides a new basis for designing novel therapeutic strategies.