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

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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.