Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients' outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients' outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.

中文翻译：

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508 名患者的全基因组测序确定了与食管鳞状细胞癌预后不良相关的关键分子特征。

食管鳞状细胞癌 (ESCC) 是一种预后不良的癌症类型，对其分子病因学的了解有限。使用 508 个 ESCC 基因组，我们确定了五个新的显着突变基因，并发现了与转移和患者结果相关的突变特征簇。一些功能分析表明 NFE2L2 可能在 ESCC 中充当肿瘤抑制因子，并且 NFE2L2 的突变可能会损害其肿瘤抑制功能，甚至赋予致癌活性。此外，我们发现 NFE2L2 突变与 ESCC 预后不良显着相关。我们还确定了潜在的非编码驱动突变，包括 SLC35E2 启动子区域的热点突变，这些突变与较差的生存率相关。大约 5.9% 和 15。2% 的患者分别具有高肿瘤突变负担或可操作突变，并且可能受益于免疫治疗或靶向治疗。我们发现了临床相关的编码和非编码基因组改变，并揭示了三种主要的亚型，可以有力地预测患者的结果。总的来说，我们报告了最大的 ESCC 基因组分析数据集，可用于开发用于诊断和治疗的 ESCC 特异性生物标志物。