RESUMO
Non-small cell lung cancer (NSCLC) is often driven by mutations in the epidermal growth factor receptor (EGFR) gene. However, rare mutations such as G719X and S768I lack standard anti-EGFR targeted therapies. Understanding the structural differences between wild-type EGFR and these rare mutants is crucial for developing EGFR-targeted drugs. We performed a systematic analysis using molecular dynamics simulations, essential dynamics (ED), molecular mechanics Poisson-Boltzmann surface area, and free energy calculation methods to compare the kinetic properties, molecular motion, and free energy distribution between wild-type EGFR and the rare mutants' structures G719X-EGFR, S768I-EGFR, and G719X + S768I-EGFR. Our results showed that S768I-EGFR and G719X + S768I-EGFR have higher global and local conformational flexibility and lower thermal and global structural stability than WT-EGFR. ED analysis revealed different molecular motion patterns between S768I-EGFR, G719X + S768I-EGFR, and WT-EGFR. The A-loop and αC-helix, crucial structural elements related to the active state, showed a tendency toward active state development, providing a molecular mechanism explanation for NSCLC caused by EGFR S768I and EGFR G719C + S768I mutations. The present study may be helpful in the development of new EGFR-targeted drugs based on the structure of rare mutations. Our findings may aid in developing new targeted treatments for patients with EGFR S768I and EGFR G719X + S768I mutations.
RESUMO
BACKGROUND: Xuanwei and Fuyuan are rural counties, located in the late Permian coal poly area of eastern Yunnan and western Guizhou, where lung cancer mortality rates are among the highest in the China, with similarity for both men and women, younger age at diagnosis and death, and higher in rural areas than in urban areas. In this paper, long-term follow-up of lung cancer cases in local peasants was conducted to observe their survival prognosis and its influencing factors. METHODS: Data of patients diagnosed with lung cancer from January 2005 to June 2011, who had lived in Xuanwei and Fuyuan counties for many years, were collected from 20 hospitals at the local provincial, municipal and county levels. To estimate survival outcomes, individuals were followed up until the end of 2021. The 5-year, 10-year and 15-year survival rates were estimated using the Kaplan-Meier method. Survival differences were examined with Kaplan-Meier curves and Cox proportional hazards models. RESULTS: A total of 3,017 cases were effectively followed up (2,537 peasants and 480 non-peasants). The median age at diagnosis was 57 years, and the median follow-up time was 122 months. During the follow-up period, 2,493 cases (82.6%) died. The distribution of cases by clinical stage was as follows: stage I (3.7%), stage II (6.7%), stage III (15.8%), stage IV (21.1%) and unknown stage (52.7%). Treatment at the provincial, municipal and county-level hospitals accounted for 32.5%, 22.2% and 45.3%, respectively, and surgical treatment was performed in 23.3% of cases. The median survival time was 15.4 months (95%CI: 13.9-16.1), and the 5-year, 10-year and 15-year overall survival rates were 19.5% (95%CI: 18.0%-21.1%), 7.7% (95%CI: 6.5%-8.8%) and 2.0% (95%CI: 0.8%-3.9%), respectively. Peasants with lung cancer had a lower median age at diagnosis, higher proportion residing in remote rural areas, and higher use of bituminous coal as a household fuel. They also have a lower proportion of early-stage cases, treatment at provincial or municipal hospitals, and surgical treatment, leading to poorer survival outcomes (HR=1.57). Even when considering factors such as gender, age, residential location, clinical stage at diagnosis, histological type, hospital level of service, and surgical intervention, peasants still exhibit a survival disadvantage. Multivariable Cox model analysis comparing peasants and non-peasants reveals that surgical intervention, tumor-node-metastasis (TNM) stage, and hospital level of service are common factors influencing survival prognosis, while the use of bituminous coal as a household fuel, hospital level of service and adenocarcinoma (compared to squamous cell carcinoma) are independent prognostic factors for lung cancer survival among peasants. CONCLUSIONS: The lower lung cancer survival rate among peasants is associated with their lower socioeconomic status, lower proportion of early-stage diagnoses, lower proportion of surgical interventions, and treatment at provincial-level hospitals. Furthermore, the impact of other factors such as high-risk exposure to bituminous coal pollution on survival prognosis requires further investigation.
