Comprehensive analysis reveals distinct mutational signature and its mechanistic insights of alcohol consumption in human cancers.

Alcohol consumption is a critical risk factor for multiple types of cancer. A genome can be attacked and acquire numerous somatic mutations in the environment of alcohol exposure. Mutational signature has the capacity illustrating the complex somatic mutation patterns in cancer genome. Recent studies have discovered distinct mutational signatures associating with alcohol consumption in liver and esophageal cancers. However, their prevalence among diverse cancers, impact of genetic background and origin of alcohol-induced mutational signatures remain unclear. By a comprehensive bioinformatics analysis on somatic mutations from patients of four cancer types with drinking information, we identified nine mutational signatures (signatures B-J), among which signature J (similar to COSMIC signature 16) was distinctive to alcohol drinking. Signature J was associated with HNSC, ESCA and LIHC but not PAAD. Interestingly, patients with mutated allele rs1229984 in ADH1B had lower level of signature J while mutated allele rs671 in ALDH2 exhibited higher signature J abundance, suggesting acetaldehyde is one cause of signature J. Intriguingly, somatic mutations of three potential cancer driver genes (TP53, CUL3 and NSD1) were found the critical contributors for increased mutational load of signature J in alcohol consumption patients. Furthermore, signature J was enriched with early accumulated clonal mutations compared to mutations derived from late tumor growth. This study systematically characterized alcohol-related mutational signature and indicated mechanistic insights into the prevalence, origin and gene-environment interaction regarding the risk oncogenic mutations associated with alcohol intake.