A mutational signature associated with alcohol consumption and prognostically mutated driver genes in esophageal squamous cell carcinoma

Aim: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. Herein, we elucidated significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC. 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 previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike Cu003eT at CpG, APOBEC overactive Cu003eT at TpCp[A/T], and a signature featured by Tu003eC substitution. The Tu003eC mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P Conclusions: We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutation and TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC. Citation Format: Xiangchun Li, Mengyao Wang, Meng Yang, Hongji Dai, Baifeng Zhang, Wei Wang, Xinlei Chu, Xin Wang, Hong Zheng, Ruifang Niu, Wei Zhang, Kexin Chen. A mutational signature associated with alcohol consumption and prognostically mutated driver genes in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3405.