Abstract
BACKGROUND: Lung cancer is the most prevalent cancer worldwide and accounts for approximately 20% of cancer-related death in China every year. High-grade lung cancer poses a significant threat to patients, and developing a novel treatment for these patients requires an understanding of its underlying mechanism. METHODS: Chinese patients with lung cancer were enrolled. The tumor samples were collected by surgery or puncture and applied for next-generation sequencing. A panel of pan-cancer genes was targeted, and the sequencing depth was set to over 1,000 to improve the sensitivity of detecting mutations. Short-length mutations (substitution, insertion, and deletion), copy number variation, and gene fusion were called. Gene mutations were compared between low-grade, middle-grade, and high-grade tumors using Fisher's exact test. The enriched pathways in each grade of tumors were also inferred. RESULTS: The study included 173 Chinese patients with non-small cell lung cancer, of whom 98 (56.6%) patients were female and 75 (43.4%) were male, with a mean age of 56.8 years. All patients were microsatellite stable; 66.4% were at the early stages (Stages 0, I, and II) with a tumor mutational burden of approximately 2.5 (confidence interval = [0, 48.3]). Compared to low-grade tumors, high-grade tumors had a significantly higher percentage of mutations in TP53 (75.9% vs 34.4%, p = 1.86e-3) and PIK3CA (24.1% vs. 0%, p = 3.58e-3). Pathway analysis found that high-grade tumors were enriched with mutations in bacterial invasion of epithelial cells (31% vs. 0%, p = 5.8e-4), Epstein-Barr virus infection (79.3% vs. 37.5%, p = 1.72e-3), and the Wnt signaling pathway (75.9% vs. 34.4%, p = 1.91e-3). High-grade tumors had a significantly higher tumor mutational burden than low-grade tumors (p-value = 0.0017). However, actionable mutations with high-level evidence were lower in high-grade tumors. CONCLUSION: Patients with high-grade tumors from lung cancer may be more affected by bacteria and Epstein-Barr virus than low-grade tumors. High-grade tumors were specially mutated in TP53 and PIK3CA and may benefit more from immunotherapy. Further research on the underlying mechanism of high-grade lung cancer is necessary to develop new therapeutic options. Lung cancer, tumor grade, genomic mutations, Epstein-Barr virus, pathway analysis.