Ethnicity-specific association between TERT rs2736100 (A > C) polymorphism and lung cancer risk: a comprehensive meta-analysis.

The rs2736100 (A > C) polymorphism of the second intron of Telomerase reverse transcriptase (TERT) has been confirmed to be closely associated with the risk of Lung cancer (LC), but there is still no unified conclusion on the results of its association with LC. This study included Genome-wide association studies (GWAS) and case-control studies reported so far on this association between TERT rs2736100 polymorphism and LC to clarify such a correlation with LC and the differences in it between different ethnicities and different types of LC. Relevant literatures published before May 7, 2022 on 'TERT rs2736100 polymorphism and LC susceptibility' in PubMed, EMbase, CENTRAL, MEDLINE databases were searched through the Internet, and data were extracted. Statistical analysis of data was performed in Revman5.3 software, including drawing forest diagrams, drawing funnel diagrams and so on. Sensitivity and publication bias analysis were performed in Stata 12.0 software. The C allele of TERT rs2736100 was associated with the risk of LC (Overall population: [OR] = 1.21, 95%CI [1.17, 1.25]; Caucasians: [OR] = 1.11, 95%CI [1.06, 1.17]; Asians: [OR] = 1.26, 95%CI [1.21, 1.30]), and Asians had a higher risk of LC than Caucasians (C vs. A: Caucasians: [OR] = 1.11 /Asians: [OR]) = 1.26). The other gene models also showed similar results. The results of stratified analysis of LC patients showed that the C allele was associated with the risk of Non-small-cell lung carcinoma (NSCLC) and Lung adenocarcinoma (LUAD), and the risk of NSCLC and LUAD in Asians was higher than that in Caucasians. The C allele was associated with the risk of Lung squamous cell carcinoma (LUSC) and Small cell lung carcinoma(SCLC) in Asians but not in Caucasians. NSCLC patients ([OR] = 1.27) had a stronger correlation than SCLC patients ([OR] = 1.03), and LUAD patients ([OR] = 1.32) had a stronger correlation than LUSC patients ([OR] = 1.09).In addition, the C allele of TERT rs2736100 was associated with the risk of LC, NSCLC and LUAD in both smoking groups and non-smoking groups, and the risk of LC in non-smokers of different ethnic groups was higher than that in smokers. In the Asians, non-smoking women were more at risk of developing LUAD. The C allele of TERT rs2736100 is a risk factor for LC, NSCLC, and LUAD in different ethnic groups, and the Asian population is at a more common risk. The C allele is a risk factor for LUSC and SCLC in Asians but not in Caucasians. And smoking is not the most critical factor that causes variation in TERT rs2736100 to increase the risk of most LC (NSCLC, LUAD). Therefore, LC is a multi-etiological disease caused by a combination of genetic, environmental and lifestyle factors.

Disruptive and Truncating TP53 Mutations Are Associated with African-Ancestry and Worse Prognosis in Brazilian Patients with Lung Adenocarcinoma.

INTRODUCTION: TP53 is the most frequently mutated gene in lung tumors, but its prognostic role in admixed populations, such as Brazilians, remains unclear. In this study, we aimed to evaluate the frequency and clinicopathological impact of TP53 mutations in non-small cell lung cancer (NSCLC) patients in Brazil. METHODS: We analyzed 446 NSCLC patients from Barretos Cancer Hospital. TP53 mutational status was evaluated through targeted next-generation sequencing (NGS) and the variants were biologically classified as disruptive/nondisruptive and as truncating/nontruncating. We also assessed genetic ancestry using 46 ancestry-informative markers. Analysis of lung adenocarcinomas from the cBioportal dataset was performed. We further examined associations of TP53 mutations with patients' clinicopathological features. RESULTS: TP53 mutations were detected in 64.3% (n = 287/446) of NSCLC cases, with a prevalence of 60.4% (n = 221/366) in lung adenocarcinomas. TP53 mutations were associated with brain metastasis at diagnosis, tobacco consumption, and higher African ancestry. Disruptive and truncating mutations were associated with a younger age at diagnosis. Additionally, cBioportal dataset revealed that TP53 mutations were associated with younger age and Black skin color. Patients harboring disruptive/truncating TP53 mutations had worse overall survival than nondisruptive/nontruncating and wild-type patients. CONCLUSION: TP53 mutations are common in Brazilian lung adenocarcinomas, and their biological characterization as disruptive and truncating mutations is associated with African ancestry and shorter overall survival.

Disparate outcomes in nonsmall cell lung cancer by immigration status.

OBJECTIVE: The purpose of this study was to evaluate overall survival (OS) outcomes by race, stratified by country of origin in patients diagnosed with NSCLC in California. METHODS: We performed a retrospective analysis of nonsmall cell lung cancer (NSCLC) patients diagnosed between 2000 and 2012. Race/ethnicity was defined as White (W), Black (B), Hispanic (H), and Asian (A) and stratified by country of origin (US vs. non-US [NUS]) creating the following patient cohorts: W-US, W-NUS, B-US, B-NUS, H-US, H-NUS, A-US, and A-NUS. Three multivariate models were created: model 1 adjusted for age, gender, stage, year of diagnosis and histology; model 2 included model 1 plus treatment modalities; and model 3 included model 2 with the addition of socioeconomic status, marital status, and insurance. RESULTS: A total of 68,232 patients were included. Median OS from highest to lowest were: A-NUS (15 months), W-NUS (14 months), A-US (13 months), B-NUS (13 months), H-US (11 months), W-US (11 months), H-NUS (10 months), and B-US (10 months) (p < 0.001). In model 1, B-US had worse OS, whereas A-US, W-NUS, B-NUS, H-NUS, and A-NUS had better OS when compared to W-US. In model 2 after adjusting for receipt of treatment, there was no difference in OS for B-US when compared to W-US. After adjusting for all variables (model 3), all race/ethnicity profiles had better OS when compared to W-US; B-NUS patients had similar OS to W-US. CONCLUSION: Foreign-born patients with NSCLC have decreased risk of mortality when compared to native-born patients in California after accounting for treatments received and socioeconomic differences.

Next Generation Sequencing of Advanced Non-Small Cell Lung Cancer: Utilization Based on Race and Impact on Survival.

BACKGROUND: Next generation sequencing (NGS) of tumor of patients with advanced non-small cell lung cancer (NSCLC) is now a standard of care that informs the clinician on the best therapeutic approach for their patients. The purpose of our study was to investigate the overall impact of NGS testing on survival as well as potential racial differences in utilization, therapeutic decision, and genomic alterations. METHOD: Using a large institutional database, 928 patients with stage IV NSCLC were identified. NGS testing using Foundation One platform was used. Clinical and genomic characteristics were compared by race. We used a propensity-modeling technique to compare groups that were sequenced or not in terms of overall survival. Time to event data was analyzed using Kaplan-Meier method and Cox model. RESULTS: A total of 295 patients underwent NGS. Patients undergoing NGS testing had significantly longer survival of 25.3 months versus those who did not undergo sequencing with a median survival of 14.6 months (P = .002) irrespective if they received targeted therapy or not. There was no difference in terms of NGS utilization based on race (P = .32). African American individuals had significantly higher rates of ALK rearrangements and mutations in PBRM1, SETD2, TSC2, and FBXW7. CONCLUSION: Our study demonstrates that within a large single institution there is no racial difference in NGS utilization and that NGS testing directly impacts survival. We identify a number of differences in genomic findings between African American and white individuals.

Racial and Ethnic Disparities in Lung Adenocarcinoma Survival: A Competing-Risk Model.

BACKGROUND: Race/ethnicity-specific disparities in lung cancer survival have been investigated extensively. However, more studies concentrating on lung adenocarcinoma (ADC), especially those using a competing-risk model, are needed. We examined race/ethnicity-specific differences in lung ADC survival. PATIENTS AND METHODS: Patients with ADC diagnosed from 2004 to 2015 were identified from the Surveillance, Epidemiology, and End Results program. Race/ethnicity was categorized into 4 groups: non-Hispanic white (NHW), non-Hispanic black (NHB), non-Hispanic Asian/Pacific Islander (NHAPI), and Hispanic. Lung cancer-specific mortality (LCSM) and other cause-specific mortality (OCSM) were evaluated using a competing-risk model. RESULTS: On multivariate analysis, NHB patients experienced slightly lower LCSM (subdistribution hazard ratio, 0.96; 95% confidence interval, 0.94-0.98) and higher OCSM (subdistribution hazard ratio, 1.16; 95% confidence interval, 1.11-1.22) compared with NHW patients in the stage IV group. No significant differences were found in LCSM and OCSM between the NHB and NHW patients with early-stage ADC (stage I or II). Both NHAPI and Hispanic patients experienced lower OCSM and LCSM compared with the NHW patients. Additionally, NHB patients with stage IV tumors had a greater mortality risk of cardiovascular disease and a lower risk of chronic obstructive pulmonary disease than NHW patients. CONCLUSIONS: The source of racial/ethnic survival disparities that exist between NHB and NHW patients was mainly found in patients with stage IV ADC. Reducing the greater mortality rate of cardiovascular disease among NHB patients and chronic obstructive pulmonary disease among NHW patients would be conducive to narrowing the racial/ethnic gaps. Further research is warranted to determine additional influencing factors, especially among patients with stage IV ADC.

LncRNA NEAT1 polymorphisms and lung cancer susceptibility in a Chinese Northeast Han Population: A case-control study.

BACKGROUND: Long non-coding RNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) is a novel lncRNA localized specifically to nuclear paraspeckles. The study analyses the association between NEAT1 genetic polymorphisms and the susceptibility of lung cancer in a Chinese Northeast Population. METHODS: The NEAT1 rs512715 and rs2239895 genetic polymorphisms were genotyped in 462 lung cancer cases and 559 controls by a Real-Time Polymerase Chain Reaction (PCR) with the TaqMan discrimination assay. RESULTS: Our study found that the polymorphisms of two SNPs increased or decreased the risk of lung cancer were not obvious, but statistical significance in non-small cell lung cancer and lung squamous cell carcinoma can be observed. Compared with homozygous CC genotype carriers, the GC genotype of rs2239895 was positively related to the risk of lung squamous cell carcinoma (OR 1.805, 95% CI, 1.168-2.789, P = 0.008). Similarly, associations between rs2239895 and lung squamous cell carcinoma risk were found (CC + GC vs. GG, OR 1.668, 95%CI, 1.093-2.545, P = 0.018) in dominant model. In stratified analysis for age, rs2239895 GC genotype was observed to increase the risk of non-small-cell lung cancer compared with CC genotype (OR 1.562, 95%CI, 1.029-2.371, P = 0.036). However, the study showed that negative correlation the lung cancer risk and rs512715 polymorphisms. There was no remarkable relationship between the both additive and multiplicative model about the two SNPs. CONCLUSIONS: The polymorphisms rs2239895 were associated with the risk of lung squamous cell carcinoma. The interaction between the two SNPs and the cigarette smoking was no notable difference.

Comparative analysis of co-occurring mutations of specific tumor suppressor genes in lung adenocarcinoma between Asian and Caucasian populations.

INTRODUCTION: Mutated tumor suppressor genes (TSG) such as TP53, STK11, and MGA are widely-reported. We hypothesized the presence of single mutation or co-occurring mutations in these specific genes may represent a significant therapeutic target for lung adenocarcinoma. METHODS: We sequenced lung adenocarcinoma samples from 677 East-Asian patients, combined them with those from cBioPortal public database (including TCGA) and performed a comparative analysis between Asian and Caucasian populations. RESULTS: East-Asian lung adenocarcinomas presented distinct driver-mutational distribution compared to that of Caucasians (79% vs 56%, p < 0.001). Similar results were observed in TSG mutations of TP53 (35% vs 46%, p = 0.150), STK11 (4% vs 17%, p = 0.006) and MGA (10% vs 4%, p = 0.166). Compared with none-mutational cases, the patients harboring TSG mutations are more likely to be male (p = 0.009), smokers (p < 0.001), and more advanced disease (p = 0.004). In addition, the TSG-mutated tumors had poorer differentiation (p < 0.001), and more likely to be solid or micropapillary-predominant adenocarcinomas (p < 0.001). Survival analysis showed that both overall survival (OS, p < 0.001) and post-recurrence survival (PRS, p < 0.001) became worse with the accumulation of TSG mutations. However, the prognostic variety was not found in Caucasian patients. Moreover, multivariate analysis proved the accumulation of TSG mutations independently predicts both unfavorable OS (HR = 0.435, 95% CI 0.245-0.774, p = 0.005) and PRS (HR = 0.491, 95% CI 0.269-0.894, p = 0.020) in East-Asian patients, adjusting all other survival-associated factors. CONCLUSIONS: Co-occurring mutations of specific TSGs define unfavorable subgroups of lung adenocarcinoma, implying that the tumor promotion mechanisms contribute to the heterogeneity in tumor evolution. However, the Caucasian population did not show the same results, providing insights into the molecular basis underlying the striking racial disparities of this disease and evidence for different gene-panel designs for different population in the purpose of targeted therapy.