Single-nucleotide polymorphisms of nucleotide excision repair genes and their association with overall survival in North Indian lung cancer patients treated with platinum-based doublet chemotherapy.

Background: The aim of the study is to understand the association of Nucleotide excision repair (NER) inter-genetic polymorphic combinations with overall survival (OS) in lung cancer as well as its histological subtypes in the North Indian population. Materials and Methods: Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. For survival analysis, the univariate Kaplan-Meier and multivariate Cox regression model were applied. Recursive partitioning method, survival analysis tree was applied to study unfavorable genotypic combinations in NER single-nucleotide polymorphisms. Results: Combinatorial studies suggested no association between polymorphic combinations of NER genes and OS in lung cancer patients. When stratified as per lung cancer histological subtypes, adenocarcinomas patients with XPG 670 and XPC 499 polymorphism a significant increase in OS in combined heterozygous and mutant genotype with a lower hazardous ratio (Hazard Ratio1 (HR) = 0.20; P = 0.004). Small-cell lung carcinoma (SCLC) patients with XPF 11985A>G and XPD Arg156Arg polymorphism showed a 4-fold hazard ratio among heterozygous genotype (HR1 = 4.84; P = 0.007) where no significant results are obtained in patients suffering from squamous cell carcinoma histological subtypes. STREE showed XPG Asp1104His (W), XPD Lys751Gln (H + M), XPF Arg415Gln (H + M) genotype was associated with a lower hazard ratio (P = 0.0007) showing survival of 11.6 months when compared with the reference (median survival time = 3.52). Conclusion: It can be concluded that SCLC patients with polymorphic combinations of the NER pathway were associated with a higher risk of mortality. STREE depicted the association of NER polymorphic combinations with a lower hazard ratio predicting them to be a good prognostic factor for lung cancer.

The multi-faceted high order polymorphic synergistic interactions among nucleotide excision repair genes increase the risk of lung cancer in North Indians.

It is evident that gene-gene interactions are pervasive in the determination of the susceptibility of human diseases. Polymorphisms in nucleotide excision repair pathway (NER) genes can cause variations in the repair capacity and therefore, might lead to increase in susceptibility towards lung cancer through complex gene-gene and gene-smoking interactions. Logistic regression analysis, along with high order genetic interaction were analyzed using data mining tools such as multifactor dimensionality reduction (MDR) and classification and regression tree analysis (CART). Overall, a protective effect was reported when a combinatorial effect of SNPs were studied by applying logistic regression analysis. Multifactor dimensionality reduction (MDR) analysis, revealed that the four factor model i.e. XPC K939Q, XPA 5'UTR, XPG F670W and XPG D1104H had the best ability to predict lung cancer risk (CVC = 100, p < 0.0001). While a two factor model, including smoking and XPG F670W suggested smoking was associated with the risk of developing lung cancer (CVC = 100, p < 0.0001). Individually XPG F670W was identified as the primary risk factor. In classification and regression tree analysis (CART), we observed a 6-fold risk for SCLC patients carrying XPA 5'UTR (M), XPD K751Q (W) (OR: 6.20; 95%CI: 2.40-16.01, p = 0.0001).Polymorphic NER genes might jointly modulate lung cancer risk through gene-gene and gene-smoking interaction.

XPG polymorphisms and their association with lung cancer susceptibility, overall survival and response in North Indian patients treated with platinum-based doublet chemotherapy.

AIM: The study investigates association of XPG polymorphism with lung cancer susceptibility, overall survival and clinical outcomes in North Indian population. RESULTS: A significant protective effect was observed for 2228959 C/A polymorphism with lung cancer and its histological subtypes. An increased hazard ratio (HR) was observed in 17655 G/C variant among small-cell lung carcinoma patients with mutant genotype (HR: 2.55; p = 0.05). Individuals treated with irinotecan-cisplatin/carboplatin regimen showed a longer survival time (HR1: 0.04; median survival time [MST]: 32.5 months). Subjects treated with pemetrexed-cisplatin/carboplain regimen were associated with higher mortality rate in lung cancer patients (HR1: 1.83;  MST: 9.13 months). CONCLUSION: 2228959 C/A polymorphism contributes to protective effect in lung cancer patients. 2228959 C/A polymorphism might be associated with favorable prognosis in lung cancer risk.

XPF polymorphism toward lung cancer susceptibility and survival in patients treated with platinum-based chemotherapy.

AIM: To evaluate the association of three XPF polymorphic variants (673 C>T, 11985 A>G, G415A) with lung cancer, overall survival and clinical response in North Indians. METHODS: Genotyping was performed using PCR-restriction fragment length polymorphism. RESULTS: A total of 673 C>T polymorphism was associated with 1.5-fold increased lung cancer risk for heterozygous genotype (CT; p = 0.03). Adenocarcinoma patients with 673 C>T polymorphism carrying heterozygous genotype (CT) had a lower hazard ratio (p = 0.01). Classification and regression tree analysis predicted XPF 673 C>T (M) as the strongest risk factor for the lung cancer (p = 0.003). For 11985 A>G polymorphism, lung cancer subjects treated with irinotecan cisplatin/carboplatin regimen having heterozygous genotype (AG) was associated with high mortality risk (p = 0.0001). CONCLUSION: 673 C>T polymorphism was associated with increased lung cancer risk.

Association of XPA Polymorphisms Towards Lung Cancer Susceptibility and its Predictive Role in Overall Survival of North Indians.

The present study investigated the role of Xeroderma pigmentosum group A (XPA) polymorphism (A23G and G709A) with lung cancer risk and its association with overall survival in North Indians. 370 cases and 370 controls were investigated to evaluate association between XPA polymorphism (A23G and G709A) with lung cancer risk using logistic regression analysis. A follow-up study was also conducted for 291 lung cancer cases illustrating correlation between overall survival in lung cancer patients and XPA variants. GG genotype showed an increased lung cancer risk (p = 0.0007) for A23G polymorphism whereas G709A polymorphism was associated with significant protective effect in heterozygous (AG) subjects (p = 0.001). When stratified according to smoking status an increased risk for lung cancer was observed for GG genotype in A23G polymorphism (p = 0.0002). A poor survival in females carrying variant genotype (GG) was observed (p = 0.001; MST = 4.16 months) for A23G polymorphism. Adenocarcinoma patients with heterozygous genotype showed an increased hazard ratio (p = 0.02) for A23G polymorphism. G709A was associated with a reduced hazard ratio marking a better survival among mutant females (HR 0.17; p = 0.05; MST = 18.63 months). It can be concluded that A23G polymorphism might contribute to increased lung cancer risk in North Indian population emphasizing on poor survival among females. G709A polymorphism might result in protective effect in lung cancer subjects. The present study had a low sample size but it could act as reference for the large sample studies in future.

XPC Polymorphism and Risk for Lung Cancer in North Indian Patients Treated with Platinum Based Chemotherapy and Its Association with Clinical Outcomes.

Xeroderma pigmentosum complementation group C plays an important role in the human repair system. As reported in previous studies its polymorphism are associated with lung cancer susceptibility. The purpose of this study is to investigate the association of XPC gene with lung cancer susceptibility, overall response and clinical outcomes amongst North Indians. A hospital based study of 370 lung cancer cases and 370 healthy controls was conducted and genotypes were determined using PCR-RFLP assay. Results were assessed using logistic linear regression adjusted for age, sex and smoking status. Survival analysis was conducted using Kaplan-Meier survival analysis and Cox regression analysis. The treatment outcomes of 167 lung cancer patients treated with platinum based chemotherapy were evaluated.The mutant genotypic variant of XPC Lys939Gln has been associated with elevated risk of lung cancer(OR:2.30;95%CI:1.41-3.73;p=0.0007) whereas XPC Ala499Val showed a highly protective effect (OR:0.25;95%CI:0.10-0.63;p=0.003). The mutant genotype of XPC Lys939Gln presented a higher risk of developing lung cancer in heavy smokers (OR: 3.71; 95%CI:1.46-9.45; p=0.005). The survival analysis presented that heterozygous genotype showed least survival in comparison with mutant genotype in XPC Ala499Val genetic variant whereas no significant association was observed in XPC Lys939Gln. In conclusion, XPC Lys939Gln is associated with significant risk towards the lung cancer whereas on contrary XPC Ala499Val shows a protective effect.

Xeroderma pigmentosum complementation group D polymorphism toward lung cancer susceptibility survival and response in patients treated with platinum chemotherapy.

AIM: The study investigated role of xeroderma pigmentosum complementation group D (XPD) single nucleotide polymorphisms in modulating lung cancer risk and its association with overall survival and clinical outcomes. METHODS:  XPD polymorphisms were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS:  CC genotype of A751C polymorphism was associated with an increased lung cancer risk (p = 0.01). Classification and Regression Tree (CART) analysis depicted C156A as the major contributing factor. Patients having CC, treated with irinotecan-cisplatin/carboplatin regimen showed a better survival (median survival time = 25.2) whereas a poor survival was for XPD G312A. Similarly, patients treated with pemetrexed and carrying heterozygous genotype of G312A polymorphism had a poor survival (p = 0.01). CONCLUSION:  A751C and G312A act as a predictive marker in lung cancer patients treated with platinum chemotherapy. These findings might facilitate therapeutic decisions for individualized therapy in lung cancer patient. [Formula: see text].