Genomic Profiling Identified a Mutational Signature Related to Female in Nonsmoking Lung Adenocarcinoma.

Purpose: This study aimed to illustrate mutational characteristics in nonsmoking lung adenocarcinoma (LUAD) and to explore its relationship with clinical factors. Materials and Methods: We included 86 nonsmokers with LUAD and downloaded the clinical information, whole exome sequencing, and RNA sequencing data from cBioPortal and The Cancer Genome Atlas (TCGA) website. NMF algorithm, "SomaticSignatures," and "DeconstructSigs" were used to reconstruct and infer new mutational signature. The similarity between Catalogue of Somatic Mutations in Cancer (COSMIC) and reconstructed mutational signature was measured by cosine similarity. The enrichment status of signaling pathways was derived by Gene Set Enrichment Analysis. "pRRophetic" package was used to predict the sensitivity of adjuvant drug for cancer treatments. Results: The most frequent driver genes in nonsmoking LUAD were epidermal growth factor receptor (EGFR) (59% in cBioPortal cohort, 68% in Fujian nonsmoking LUAD cohort). We identified three new mutation signatures of LUAD in nonsmokers and identified S2 as the most enriched signature in these nonsmokers with LUAD. In cBioPortal and Fujian nonsmoking LUAD cohort, the proportion of S2 was higher in females (p < 0.05) and patients with tumor mutational burden (TMB) (p < 0.01). Similar results were observed in nonsmoking TCGA-LUAD cohort (pfemale=0.0013, pTMB < 0.001). OXIDATIVE_PHOSPHORYLATION signaling pathway was most enriched in S2-enriched group (NES=1.63). S2-enriched group had higher mutation rate of EGFR (p=0.003) and more drug sensitivity to metformin (p=0.035). Conclusion: We identified a new mutational signature (S2) which is most enriched in LUAD in nonsmokers and related to female and low-TMB. S2 mutational signature may help reveal female-related mutagenesis mechanisms and develop strategies for therapeutic of never-smoker lung adenocarcinoma.