Background Esophageal squamous cell carcinoma (ESCC) is often diagnosed at an advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. The objective was to elucidate significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC. Patients and methods Three MutSig algorithms (i.e. MutSigCV, MutSigCL and MutSigFN) and '20/20+' ratio-metric were employed to identify SMGs. Nonnegative matrix factorization was used to decipher mutational signatures. Kaplan-Meier survival analysis, multivariate Cox and logistic regression models were applied to analyze association between mutational features and clinical parameters. Results We identified 26 SMGs, including 8 novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8 and BAP1) and 18 that have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike C>T at CpG, APOBEC overactive C>T at TpCp[A/T], and a signature featured by T>C substitution. The T>C mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P < 0.001). This alcohol consumption signature was also observed in liver cancer and head and neck squamous cell carcinoma, and its mutational activity was substantially higher in samples with mutations in TP53. Survival analysis revealed that TENM3 mutations (HR: 5.54; CI: 2.68-11.45; P < 0.001) and TP53 hotspot mutation p.R213* (HR: 3.37; CI: 1.73-8.06; P < 0.001) were significantly associated with shortened survival outcome. The association remained statistically significant after controlling for age, gender, TNM stage and tumor grade. Conclusions We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.

中文翻译：

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食道鳞状细胞癌中与饮酒有关的突变特征和预后显着突变的驱动基因。

背景食管鳞状细胞癌（ESCC）通常被诊断为晚期且无法治愈。有关ESCC中驱动基因和预后因素的信息仍不完整。目的是阐明ESCC中的显着突变基因（SMG），突变特征和预后因子。患者和方法采用了三种MutSig算法（即MutSigCV，MutSigCL和MutSigFN）和'20 / 20 +'比率量度来识别SMG。非负矩阵分解用于解密突变特征。应用Kaplan-Meier生存分析，多元Cox和Logistic回归模型分析突变特征与临床参数之间的关联。结果我们鉴定了26种SMG，包括8种新颖的（NAV3，TENM3，PTCH1，TGFBR2，RIPK4，PBRM1，USP8和BAP1）和18种先前已报道过的SMG。在ESCC中，三个突变特征被确定为普遍存在，包括CpG处的钟状C> T，TpCp [A / T]处的APOBEC活性过高的C> T以及以T> C替代为特征的特征。T> C突变特征与饮酒量显着相关（OR：3.59； 95％CI：2.30-5.67； P <0.001）。在肝癌和头颈部鳞状细胞癌中也观察到这种酒精消耗信号，并且其突变活性在TP53突变的样品中明显更高。生存分析显示TENM3突变（HR：5.54; CI：2.68-11.45; P <0.001）和TP53热点突变p.R213 *（HR：3.37; CI：1.73-8.06; P <0.001）与缩短的生存期显着相关结果。在控制了年龄，性别，TNM分期和肿瘤分级。结论我们在ESCC中发现了几种新的SMG，并定义了与饮酒有关的突变特征。TENM3突变和TP53热点突变p.R213 *是ESCC生存率低的独立预后因子。