Association of Topoisomerase II (TOP2A) and Dual-Specificity Phosphatase 6 (DUSP6) Single Nucleotide Polymorphisms with Radiation Treatment Response and Prognosis of Lung Cancer in Han Chinese.

BACKGROUND Mutations of DNA topoisomerase II (TOP2A) are associated with chemotherapy resistance, whereas dual-specificity phosphatase 6 (DUSP6) negatively regulates members of the mitogen-activated protein (MAP) kinase superfamily to control cell proliferation. This study assessed TOP2A and DUSP6 single nucleotide polymorphisms (SNPs) in non-small cell lung cancer (NSCLC) patients for association with chemoradiotherapy responses and prognosis. MATERIAL AND METHODS A total of 140 Chinese patients with histologically confirmed NSCLC were enrolled and subjected to genotyping of TOP2A rs471692 and DUSP6 rs2279574 using Taqman PCR. An independent sample t test was used to analyze differences in tumor regression after radiotherapy versus SNP risk factors. Kaplan-Meier curves analyzed overall survival, followed by the log-rank test and Cox proportional hazard models. RESULTS There were no significant associations of TOP2A rs471692 and DUSP6 rs2279574 polymorphisms or clinicopathological variables with response to chemoradiotherapy (p>0.05). Comparing overall survival of 87 patients with stage I-III NSCLC treated with radiotherapy or chemoradiotherapy to clinicopathological variables, the data showed that tumor regression, weight loss, clinical stage, and cigarette smoking were independent prognostic predictors (p=0.009, 0.043, 0.004, and 0.025, respectively). Tumor regression rate >0.34 was associated with patent survival versus tumor regression rate ≤0.34 (p=0.007). CONCLUSIONS TOP2A rs471692 and DUSP6 rs2279574 SNPs were not associated with chemoradiotherapy response, whereas tumor regression, weight loss, clinical stage, and cigarette smoking were independent prognostic predictors for these Chinese patients with NSCLC.

Dual Specificity Phosphatase 6 (DUSP6) Polymorphism Predicts Prognosis of Inoperable Non-Small Cell Lung Cancer after Chemoradiotherapy.

BACKGROUND: Dual-specificity phosphatase 6 (DUSP6) inactivates different target kinases to regulate cell proliferation and differentiation. Altered DUSP6 expressions or gene polymorphisms are associated with human cancer development including non-small cell lung cancer (NSCLC). DNA topoisomerase II alpha (TOP2A) regulates chromosome condensation and chromatid separation, and altered TOP2A expressions are associated with drug resistance development. This study assessed DUSP6 and TOP2A single nucleotide polymorphisms (SNPs) associated with NSCLC patient survival. METHODS: This study included 152 surgically resected NSCLC patients and 277 chemoradiotherapy treated inoperable cases. DNA samples from each patient were genotyped for DUSP6 and TOP2A SNPs. Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model were used to evaluate the association between these variants and NSCLC overall survival. RESULTS: DUSP6 rs2279574 A/A genotype was associated with significantly poor inoperable NSCLC patient overall survival (A/A vs. C/C, adjusted HR = 1.549, 95% CI = 1.019-2.355). Stratification analysis against clinical stage, histology, weight loss, and ECOG performance status revealed that the DUSP6 rs2279574 A/A variant homozygous genotype is associated with a decrease in survival of stage IV NSCLC patients compared to those with the C/C genotype (log-rank, p = 0.003). No association was found among histology, weight loss, and ECOG performance status. Moreover, there was no association of TOP2A SNPs between clinicopathological and survival data. CONCLUSIONS: Data obtained from the current study demonstrated that functional DUSP6 rs2279574 polymorphism was able to predict inoperable NSCLC patient survival after chemoradiotherapy.

SULT1A1 Arg213His polymorphism and susceptibility of environment-related cancers: a meta analysis of 5,915 cases and 7,900 controls.

The common genetic polymorphism for SULT1A1 is Arg213His polymorphism, which may affect the sulfation process of various environmental carcinogens and thus is suggested to be related to susceptibility of several cancers. However, studies on the association between SULT1A1 Arg213His polymorphism and cancer susceptibility are inconsistent. To assess the relationship between Arg213His polymorphism and environmental-related cancers systematically, we performed a meta analysis from 20 case-control studies including 5,915 cases and 7,900 controls. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of risk, we found a significant association between SULT1A1 Arg213His polymorphism and environment-related cancers (for dominant model: OR 1.22, 95% CI 1.07-1.39, P = 0.003). When stratified by ethnicity, a significant risk was observed in Asian cases, compared with controls (for dominant model: OR 1.69, 95% CI 1.17-2.43, P = 0.005). When we chose only smokers in our analysis, we also found a significantly increased risk between Arg213His polymorphism and susceptibility of environment-related cancers for participants exposed to a smoking environment. In conclusion, SULT1A1 Arg213His polymorphism, ethnicity, smoking may modulate environment-related cancer risk. Studies on gene-gene interactions in the sequential or concurrent metabolic pathway and gene-environment interactions need to be further conducted to explore the susceptibility of cancer occurrence.

Treatment patterns and survival after 18F-fluorodeoxyglucose positron emission tomography/computed tomography-guided local consolidation therapy for oligometastatic non-small cell lung cancer: a two-center propensity score-matched analysis.

PURPOSE: In this retrospective study, we evaluated the treatment patterns and survival after positron emission tomography-computed tomography (PET/CT)-guided local consolidation therapy (LCT) for oligometastatic non-small cell lung cancer (NSCLC). METHODS: We reviewed the medical records of Chinese patients with oligometastatic stage IV non-small cell lung cancer (≤ 5 metastases) who had undergone PET/CT and were eligible for systemic therapy at two centers between May 2005 and August 2019. Propensity score matching (1:1) was used to reduce selection bias and imbalanced distribution of confounding factors. RESULTS: We identified 84 eligible patients and used propensity scores to create well-matched groups of 35 patients who did or did not undergo LCT. Among all patients, the 1-year overall survival (OS) rate was 47.6% and the 2-year OS rate was 22.6%. Relative to the group that did not receive LCT, the LCT group had a significantly higher OS rate (13 months vs. 7 months, p = 0.002). The two groups had similar incidences and classifications of LCT-related side effects. In multivariable analysis, LCT was found to be strongly associated with a favorable OS (hazard ratio: 0.508, 95% confidence interval: 0.311-0.828, p = 0.001). CONCLUSION: We concluded that LCT was significantly associated with improved clinical outcomes among the Chinese patients with oligometastatic NSCLC who were eligible for systemic treatment and could undergo PET/CT evaluation.

Dual-specificity phosphatase 6 genetic variants associated with risk of lung squamous cell carcinoma in Han Chinese.

BACKGROUND: Nonsmall cell lung cancer (NSCLC) mainly contains adenocarcinoma (AC) and squamous cell carcinoma (SqCC). This study investigated single nucleotide polymorphism (SNP) of topoisomerase II alpha (TOP2A) and dual-specificity phosphatase 6 (DUSP6) in a hospital-based case and control cohort of individuals for association with risk of different histological subtypes of NSCLC. MATERIALS AND METHODS: A total of 454 (237 SqCC and 217 AC) NSCLC patients, and 454 healthy controls were recruited for analysis of TOP2A rs471692 and DUSP6 rs2279574 genotypes using the TaqMan polymerase chain reaction technique. RESULTS: TOP2A rs471692 and DUSP6 rs2279574 SNPs were in complete linkage disequilibrium; however, frequency of DUSP6 rs2279574 genotype was significantly different between the case and control, that is, DUSP6 rs2279574a/A and A/C genotypes might contribute to an increased risk of lung squamous carcinoma compared with the C/C genotype. Moreover, DUSP6 rs2279574 AA genotype was also significantly associated with advanced stages of lung cancer. In contrast, frequency of the TOP2A rs471692 genotype had no association between cases and controls (P = 0.906). Genotype frequency of DUSP6 rs2279574 was 11.9% for C/C, 43.6% for C/A, and 44.5% for A/A in the case versus 16.7% C/C, 43.4% C/A, and 39.9% A/A in the control population (χ2 = 3.136, P= 0.077 by Hardy-Weinberg equilibrium test [HWE]). The genotype frequency of TOP2A rs471692 was 50.0% for C/C, 41.6% for C/T, and 8.4% for T/T in the case versus 50.2% C/C, 43.0% C/T, and 6.8% T/T in the control populations (χ2 = 0.023, P= 0.879 by HWE test). CONCLUSION: Individuals are carrying DUSP6 rs2279574 AA and AC genotypes associated with an increased risk in developing lung squamous carcinoma in Han Chinese and with advanced NSCLC stages.

The relationship between LAPTM4B polymorphisms and cancer risk in Chinese Han population: a meta-analysis.

LAPTM4B is a newly cloned gene that shows an active role in many solid tumors progression in substantial researches, mainly through the autophage function. Accumulated studies have been conducted to determine the association of LAPTM4B polymorphism with cancer risk. While the results are inconsistent, we conducted the meta-analysis to determine the strength of the relationship. Results showed that allele*2 carriers exhibited a significantly increased risk of cancer development with comparison to allele*1 homozygote (for *1/2, OR = 1.55, 95% CI 1.367-1.758; for *2/2, OR = 2.093, 95%CI 1.666-2.629; for *1/2 + *2/2, OR = 1.806, 95%CI 1.527-2.137). We also observed a significant association between *2/2 homozygote and cancer risk with comparison to allele*1 containing genotypes (OR = 1.714, 95%CI 1.408-2.088). Allele*2 is a risk factor for cancer risk (OR = 1.487, 95%CI 1.339-1.651). Stratified analysis by tumor type exhibits the significant association of this genetic variants with various cancers. In conclusion, LAPTM4B polymorphism is associated with cancer risk and allele*2 is a risk factor.

Association of oral contraceptives use and lung cancer risk among women: an updated meta-analysis based on cohort and case-control studies.

BACKGROUND: Previous studies on the association of oral contraceptives (OC) use and lung cancer generated inconsistent findings. The aim of this study was to confirm any definite correlation between OC use and lung cancer risk. METHODS: Publications were reviewed and obtained through PubMed and EMBASE databases literature search up to November, 2013. Reference lists from retrieved articles were also reviewed. The language of publication was restricted to English. A meta-analysis was performed to evaluate the association by calculating pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 14 studies consisting of 9 case- control studies and 5 cohort studies were finally included in this meta-analysis. There was no significant association observed between OC use and lung cancer risk in the overall analysis (OR=0.91; 95% CI=0.81-1.03). There was a significant protective effect in Europe (OR=0.74; 95% CI=0.60-0.91) and a borderline significant protective effect with an adenocarcinoma histology (OR=0.90; 95% CI=0.80-1.01) in subgroup analyses. No association was observed for methodological quality of study, study design, smoking status and case number of study. CONCLUSION: This meta-analysis suggests that OC use is not likely to be associated with the risk of lung cancer at all. While a significant protective effect of OC use on lung cancer was observed in Europe, interpretation should be cautious because of the potential biases of low-quality studies. At the same time, more attention should be paid to the possible association of OC use with adenocarcinoma of lung. Our findings require further research, with well-conducted and large-scale epidemiological studies to confirm effects of OC use on lung cancer.

N-acetyltransferase 2 gene polymorphisms are associated with susceptibility to cancer: a meta-analysis.

N-acetyltransferase 2 (NAT2) is a polymorphic enzyme that plays an important role in the metabolism of various potential carcinogens. In recent years, a number of studies have been carried out to investigate the relationship between the rs1799930 and rs1799931 polymorphism in NAT2 and cancer risk in multiple populations for different types of cancer. However, the results were not consistent. Therefore, we performed a meta-analysis to further explore the relationship between NAT2 polymorphism and the risk of cancer. A total of 21 studies involving 15, 450 subjects for rs1799930 and 13, 011 subjects for rs1799931 were included in this meta-analysis. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess strength of associations. We also evaluated the publication bias and performed a sensitivity analysis. Overall, our results showed an apparent significant association between the NAT2 rs1799930 polymorphism and cancer susceptibility in Asians (GA vs. GG: OR=1.22, 95% CI=1.03-1.45; dominant model: OR=1.22, 95% CI=1.03-1.43) and population-based controls (GA vs. GG: OR=1.10, 95% CI=1.01-1.19; dominant model: OR=1.09, 95% CI=1.01-1.18). In contrast, a significant association was observed between the NAT2 rs1799931 G>A polymorphism and decreased cancer susceptibility in overall meta-analysis (AA vs. GG: OR=0.55, 95% CI=0.33-0.93; GA vs. GG: OR=1.00, 95% CI=0.88-1.14; dominant model: OR=0.97, 95% CI=0.86-1.10; recessive model: OR=0.56, 95% CI=0.34-0.94) and the Asian group (AA vs. GG: OR=0.50, 95% CI=0.26-0.94; recessive model, OR=0.50, 95% CI=0.27-0.94). We found that the NAT2 rs1799930 may be a risk factor, while the NAT2 rs1799931 polymorphism is associated with a decreased risk of cancer and is likely a protective factor against cancer development.

TP63 gene polymorphisms, cooking oil fume exposure and risk of lung adenocarcinoma in Chinese non-smoking females.

BACKGROUND: Genetic polymorphisms of TP63 have been suggested to influence susceptibility to lung adenocarcinoma development in East Asian populations. This study aimed to investigate the relationship between common polymorphisms in the TP63 gene and the risk of lung adenocarcinoma, as well as interactions of the polymorphisms with environmental risk factors in Chinese non-smoking females. METHODS: A case-control study of 260 cases and 318 controls was conducted. Data concerning demographic and risk factors were obtained for each subject. The genetic polymorphisms were determined by Taqman real-time PCR and statistical analyses were performed using SPSS software. RESULTS: For 10937405, carriers of the CT genotype or at least one T allele (CT/TT) had lower risks of lung adenocarcinoma compared with the homozygous wild CC genotype in Chinese nonsmoking females (adjusted ORs were 0.68 and 0.69, 95%CIs were 0.48-0.97 and 0.50-0.97, P values were 0.033 and 0.030, respectively). Allele comparison showed that the T allele of rs10937405 was associated with a decreased risk of lung adenocarcinoma with an OR of 0.78 (95%CI=0.60-1.01, P=0.059). Our results showed that exposure to cooking oil fumes was associated with increased risk of lung adenocarcinoma in Chinese nonsmoking females (adjusted OR=1.58, 95%CI=1.11-2.25, P=0.011). However, we did not observe a significant interaction of cooking oil fumes and TP63 polymorphisms. CONCLUSION: TP63 polymorphism might be a genetic susceptibility factor for lung adenocarcinoma in Chinese non-smoking females, but no significant interaction was found with cooking oil fume exposure.

Genetic variations in TERT-CLPTM1L genes and risk of lung cancer in a Chinese population.

BACKGROUND: This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) in telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane1-like (CLPTM1L) and lung cancer risk in a Chinese population. METHODS: We performed a hospital-based case-control study, including 980 lung cancer cases and 1000 cancer-free controls matched for age and sex. Each case and control was interviewed to collect information by well-trained interviewers. A total of 5 ml of venous blood was collected for genotype testing of TERT rs2736098 and CLPTM1L rs401681 using TaqMan methodology. RESULTS: The results revealed that the variant homozygote TERT rs2736098TT was associated with an increased risk of lung cancer (OR=2.017, 95%CI=1.518-2.681), especially lung adenocarcinoma (OR=2.117, 95%CI=1.557-3.043) and small cell carcinoma (OR=1.979, 95%CI: 1.174-3.334), compared with the TERT rs2736098CC genotype. Similar results were observed in non-smokers. CONCLUSION: The TERT rs2736098 polymorphism might affect the susceptibility to lung cancer in Chinese populations. The associations need to be verified in larger and different populations.

P53 Arg72Pro and MDM2 SNP309 polymorphisms cooperate to increase lung adenocarcinoma risk in Chinese female non-smokers: a case control study.

BACKGROUND: Cell cycle deregulation is a major component of carcinogenesis. The p53 tumor suppressor gene plays an important role in regulating cell cycle arrest, and mouse double minute 2 (MDM2) is a key regulator of p53 activity and degradation. Abnormal expression of p53 and MDM2 occurs in various cancers including lung cancer. METHODS: We investigated the distribution of the p53 Arg72Pro (rs1042522) and MDM2 SNP309 (rs2279744) genotypes in patients and healthy control subjects to assess whether these single nucleotide polymorphisms (SNPs) are associated with an increased risk of lung adenocarcinomas in Chinese female non- smokers. Genotypes of 764 patients and 983 healthy controls were determined using the TaqMan SNP genotyping assay. RESULTS: The p53 Pro/Pro genotype (adjusted OR = 1.55, 95% CI = 1.17-2.06) significantly correlated with an increased risk of lung adenocarcinoma, compared with the Arg/Arg genotype. An increased risk was also noted for MDM2 GG genotype (adjusted OR = 1.68, 95% CI = 1.27-2.21) compared with the TT genotype. Combined p53 Pro/Pro and MDM2 GG genotypes (adjusted OR = 2.66, 95% CI = 1.54-4.60) had a supermultiplicative interaction with respect to lung adenocarcinoma risk. We also found that cooking oil fumes, fuel smoke, and passive smoking may increase the risk of lung adenocarcinomas in Chinese female non-smokers who carry p53 or MDM2 mutant alleles. CONCLUSIONS: P53 Arg72Pro and MDM2 SNP309 polymorphisms, either alone or in combination, are associated with an increased lung adenocarcinoma risk in Chinese female non-smokers.