Unique genomic features and prognostic value of COSMIC mutational signature 4 in lung adenocarcinoma and lung squamous cell carcinoma

Background: Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, and prognosis. Among the signatures cataloged at COSMIC, mutational signature 4 has been linked to smoking. However, the distribution of signature 4 in Chinese lung cancer patients has not been evaluated, and its clinical value has not been evaluated. Here we survey mutational signatures in Chinese lung cancer patients and explore the relationship between signature 4 and other genomic features in the patients. Methods: We extracted mutational signatures from whole-exome sequencing data of Chinese non-small cell lung cancer patients. The data included 401 lung adenocarcinoma (LUAD) and 92 squamous cell carcinoma (LUSC). We then performed statistical analysis to search for genomic and clinical features that can be linked to mutation signatures. Results: We found signature 4 is the most frequent mutational signature in LUSC and the second most frequent in LUAD. Fifty-six LUAD and thirty-five LUSC patients were named with high signature 4 similarities (cosine similarity >0.7). These patients have shorter survival and higher tumor mutational burden comparing to those with low signature 4 similarities. Dozens of genes with single nucleotide variation, index mutations, and copy number variations were differentially enriched in the patients with high signature 4 similarities. Among these genes, CSMD3, LRP1B, TP53, SYNE1, SLIT2, FGF4, and FGF19 are common in both LUADs and LUSCs with high signature 4 similarities, showing that these genes are tightly associated with signature 4. Conclusions: The present study is the first to report a comparison in Chinese NSCLC patients with or without COSMIC mutational signature 4. These results will help find the Signature 4 related mutational process in NSCLC.