Genomic Profiling Identified a Mutational Signature Related to Female in Non-Smoking Lung Adenocarcinoma

Our aim was to illustrate mutational characteristic in non-smoking lung adenocarcinoma (LUAD) and to explore its relationship with clinical factors. We included 86 non-smokers with LUAD and downloaded the clinical information, whole exon sequencing (WES), and RNA sequencing (RNA-seq) data from cBioPortal and TCGA website. NMF algorithm, "SomaticSignatures", and "DeconstructSigs" were used to re-construct and infer new mutational signature. The similarity between COSMIC and re-constructed mutational signature was measured by cosine similarity. The enrichment status of signaling pathways was derived by GSEA. "pRRophetic" package was used to predict the sensitivity of adjuvant drug for cancer treatments. The most frequent driver genes in non-smoking LUAD were EGFR (59% in cBioPortal cohort, 68% in Fujian non-smoking LUAD cohort). We identified three new mutation signatures of LUAD in non-smokers and identified S2 as the most enriched signature in these non-smokers with LUAD. In cBioPortal and Fujian non-smoking LUAD cohort, the proportion of S2 was higher in females (p<0.05) and patients with TMB (p<0.01). Similar results were observed in non-smoking TCGA-LUAD cohort (Pfemale=0.0013, PTMB<0.001). OXIDATIVE_PHOSPHORYLATION signaling pathway were 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). We identified a new mutational signature (S2) which is most enriched in LUAD in non-smokers and related to female and low-TMB. S2 mutational signature may help revealed female-related mutagenesis mechanisms and develop strategies for therapeutic of never-smoker lung adenocarcinoma.