Tumor Mutation Signature Reveals the Risk Factors of Lung Adenocarcinoma with or Mutation.

Introduction: and mutations are frequently detected in lung adenocarcinoma (LUAD). Tumor mutational signature (TMS) determination is an approach to identify somatic mutational patterns associated with pathogenic factors. In this study, through the analysis of TMS, the underlying pathogenic factors of LUAD with and mutations were traced.

Methods: This was a retrospective study. TMS of LUAD with and mutations from the TCGA, OncoSG, and MSK datasets was determined by two bioinformatics tools, namely the "MutationalPatterns" and "FitMS" packages. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) of LUAD clinical specimens was analyzed using capillary electrophoresis.

Results: In LUAD with mutations, TMS analysis indicated that the smoking-related SBS4 signature was enriched. For LUAD with L858R mutation, the smoking-related SBS4 signature was enriched in the Western population from the TCGA database; however, the smoking-related SBS4 signature was not obvious in Asian LUAD patients. LUAD with exon19 deletion (19Del) exhibited stronger SBS15 signature, which was related to defective DNA mismatch repair. Capillary electrophoresis analysis showed that an EMAST locus was frequently instable in LUAD with 19Del. Different from the Western population, Asian LUAD patients with mutations exhibited the enrichment of SBS1, SBS2, and SBS13 signatures, which were associated with the endogenous mutation process of cytidine deamination.

Conclusions: TMS analysis reveals that smoking is associated with LUAD with mutations. Defective DNA mismatch repair and endogenous cytidine deamination are associated with LUAD with mutations, especially for the 19Del. The endogenous mutational process is stronger in Asian LUAD patients than Western LUAD patients.