Large-scale whole exome sequencing studies identify two genes,CTSL and APOE, associated with lung cancer.

Common genetic variants associated with lung cancer have been well studied in the past decade. However, only 12.3% heritability has been explained by these variants. In this study, we investigate the contribution of rare variants (RVs) (minor allele frequency <0.01) to lung cancer through two large whole exome sequencing case-control studies. We first performed gene-based association tests using a novel Bayes Factor statistic in the International Lung Cancer Consortium, the discovery study (European, 1042 cases vs. 881 controls). The top genes identified are further assessed in the UK Biobank (European, 630 cases vs. 172 864 controls), the replication study. After controlling for the false discovery rate, we found two genes, CTSL and APOE, significantly associated with lung cancer in both studies. Single variant tests in UK Biobank identified 4 RVs (3 missense variants) in CTSL and 2 RVs (1 missense variant) in APOE stongly associated with lung cancer (OR between 2.0 and 139.0). The role of these genetic variants in the regulation of CTSL or APOE expression remains unclear. If such a role is established, this could have important therapeutic implications for lung cancer patients.

Prediagnosis Smoking Cessation and Overall Survival Among Patients With Non-Small Cell Lung Cancer.

Importance: Lung cancer remains the leading cause of cancer-related death globally; non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, and cigarette smoking is the factor most significantly associated with its risk. However, little is known about the association of years since prediagnosis smoking cessation and cumulative smoking with overall survival (OS) following a lung cancer diagnosis. Objective: To characterize the association of years since smoking cessation before diagnosis and cumulative smoking pack-years with OS in patients with NSCLC in a lung cancer survivor cohort. Design, Setting, and Participants: The cohort study involved patients with NSCLC who were recruited to the Boston Lung Cancer Survival Cohort at Massachusetts General Hospital (Boston, Massachusetts) between 1992 and 2022. Patients' smoking history and baseline clinicopathological characteristics were prospectively collected through questionnaires, and OS following lung cancer diagnosis was regularly updated. Exposures: Duration of smoking cessation before a lung cancer diagnosis. Main Outcomes and Measures: The primary outcome was the association of detailed smoking history with OS following a lung cancer diagnosis. Results: Of 5594 patients with NSCLC (mean [SD] age, 65.6 [10.8] years; 2987 men [53.4%]), 795 (14.2%) were never smokers, 3308 (59.1%) were former smokers, and 1491 (26.7%) were current smokers. Cox regression analysis suggested that former smokers had 26% higher mortality (hazard ratio [HR], 1.26; 95% CI, 1.13-1.40; P < .001) and current smokers had 68% higher mortality (HR, 1.68; 95% CI, 1.50-1.89; P < .001) compared with never smokers. Log2-transformed years since smoking cessation before diagnosis were associated with significantly lower mortality among ever smokers (HR, 0.96; 95% CI, 0.93-0.99; P = .003). Subgroup analysis, stratified by clinical stage at diagnosis, revealed that former and current smokers had even shorter OS among patients with early-stage disease. Conclusions and Relevance: In this cohort study of patients with NSCLC, quitting smoking early was associated with lower mortality following a lung cancer diagnosis, and the association of smoking history with OS may have varied depending on clinical stage at diagnosis, potentially owing to the differing treatment regimens and efficacy associated with smoking exposure following diagnosis. Detailed smoking history collection should be incorporated into future epidemiological and clinical studies to improve lung cancer prognosis and treatment selection.

Sex disparities in lung cancer survival rates based on screening status.

OBJECTIVE: Low dose computed tomography (LDCT) became the standard method for lung cancer (LC) screening in 2013. However, it is unclear whether there are differences in survival rates based on sex and whether the differences depend on screening status. We aimed to evaluate the LC survival rates between females and males based on screening. MATERIAL AND METHODS: This retrospective cohort study examined data from the Boston LC Study (BLCS) between 2013 and 2021. LC screening depends on patients' demographics (age and smoking history) to determine whether a person is a high-risk individual and, therefore, undergo LDCT. Descriptive statistics were calculated for race, age, histology, smoking history, stage, and treatment. These variables' distributions were compared between sex and screening status using t-test and chi-square, respectively. Cox proportional hazards model and Kaplan-Meier curves were used to compare survival between sex and screening. Propensity score matching was applied to account for selection bias in screening when evaluating the association between screening and stage. RESULTS: A total of 1,216 LC patients were identified with a screening incidence of 9.4 %, among whom 56 % were female. Unscreened males had 1.59 times higher risk of mortality than unscreened females (P=.0002) and had a worse 5-year survival (male 50 %; 95 %CI, 0.38,0.6 vs female 70 %; 95 %CI,0.62,0.76). In contrast, there were no significant differences in survival between sexes among screened. In a balanced cohort of screened and unscreened, the odds of being diagnosed at late stages for females and smokers were 1.33 and 2.51 times that of males and nonsmokers; however, there were no statistical significance. CONCLUSION: Unscreened females had a lower risk of mortality and better survival than unscreened males, while among the screened population, there was no difference in the overall survival. These observations demonstrate the influence of sex on survival prognosis in LC when screening is not performed.