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Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients.

ABSTRACT: BACKGROUND:Small-cell lung cancer (SCLC) carries the worst prognosis among lung cancer diagnoses. Combined radiation and chemotherapy is the standard of care; however, treatment outcomes vary. Variability in the rate at which chemotherapy agents are metabolized and in the capacity of repairing DNA damage has been hypothesized to be partly responsible for the treatment response variation. Genes in the glutathione metabolism and DNA repair pathways were tested through tag single-nucleotide polymorphisms (SNPs) to assess their association with survival in SCLC. PATIENTS AND METHODS:Blood DNA from 248 patients with primary SCLC was genotyped for 419 tag SNPs from 49 genes in the glutathione and DNA repair pathways. Association analyses with patient survival were carried out at single-SNP, whole-gene, and haplotype levels after adjusting for age, gender, tumor stage, treatment modalities, and smoking history. RESULTS:Among the 375 SNPs successfully genotyped, 21 SNPs, located on 11 genes, showed significant association with survival. Whole-gene analyses confirmed 3 of the 11 genes: GSS, ABCC2, and XRCC1. Haplotype analyses of these three genes identified haplotype combinations and genomic locations underlying the observed SNP associations. CONCLUSION:Genetic variations in genes involved in the glutathione and DNA repair pathways are associated with SCLC survival.

SUBMITTER: Sun Z

PROVIDER: S-EPMC2946864 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients.

Sun Z Z Chen J J Aakre J J Marks R S RS Garces Y Y YY Jiang R R Idowu O O Cunningham J M JM Liu Y Y Pankratz V S VS Yang P P

Annals of oncology : official journal of the European Society for Medical Oncology 20100503 10

<h4>Background</h4>Small-cell lung cancer (SCLC) carries the worst prognosis among lung cancer diagnoses. Combined radiation and chemotherapy is the standard of care; however, treatment outcomes vary. Variability in the rate at which chemotherapy agents are metabolized and in the capacity of repairing DNA damage has been hypothesized to be partly responsible for the treatment response variation. Genes in the glutathione metabolism and DNA repair pathways were tested through tag single-nucleotide ...[more]

PMID: 20439344

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Project description:BACKGROUND: Current staging system for small cell lung cancer (SCLC) categorizes patients into limited- or extensive-stage disease groups according to anatomical localizations. Even so, a wide-range of survival times has been observed among patients in the same staging system. This study aimed to identify whether endobronchial mucosa invasion is an independent predictor for poor survival in patients with SCLC, and to compare the survival time between patients with and without endobronchial mucosa invasion. METHODS: We studied 432 consecutive patients with SCLC based on histological examination of biopsy specimens or on fine-needle aspiration cytology, and received computed tomography and bone scan for staging. All the enrolled patients were assessed for endobronchial mucosa invasion by bronchoscopic and histological examination. Survival days were compared between patients with or without endobronchial mucosa invasion and the predictors of decreased survival days were investigated. RESULTS: 84% (364/432) of SCLC patients had endobronchial mucosal invasion by cancer cells at initial diagnosis. Endobronchial mucosal involvement (Hazard ratio [HR], 2.01; 95% Confidence Interval [CI], 1.30-3.10), age (HR, 1.04; 95% CI, 1.03-1.06), and extensive stage (HR, 1.39; 95% CI, 1.06-1.84) were independent contributing factors for shorter survival time, while received chemotherapy (HR, 0.32; 95% CI, 0.25-0.42) was an independent contributing factor better outcome. The survival days of SCLC patients with endobronchial involvement were markedly decreased compared with patients without (median 145 vs. 290, p<0.0001). Among SCLC patients of either limited (median 180 vs. 460, p<0.0001) or extensive (median 125 vs. 207, p<0.0001) stages, the median survival duration for patients with endobronchial mucosal invasion was shorter than those with intact endobronchial mucosa, respectively. CONCLUSION: Endobronchial mucosal involvement is an independent prognostic factor for SCLC patients and associated with decreased survival days.

Project description:ObjectivesWe aimed to determine the associations of genetic polymorphisms of excision repair cross-complementation group 1 (ERCC1) rs11615, xeroderma pigmentosum group D (XPD/ERCC2) rs13181, X-ray repair cross complementing group 1 (XRCC1) rs25487, XRCC3 rs1799794, and breast cancer susceptibility gene 1 (BRCA1) rs1799966 from the DNA repair pathway and multiple drug resistance 1 (MDR1/ABCB1) rs1045642 with response to chemotherapy and survival of non-small cell lung cancer (NSCLC) in a Chinese population.Materials and methodsA total of 352 NSCLC patients were enrolled to evaluate the associations of the six SNPs with response to chemotherapy and overall survival. Logistic regressions were applied to test the associations of genetic polymorphisms with response to chemotherapy in 161 advanced NSCLC patients. Overall survival was analyzed in 161 advanced and 156 early stage NSCLC patients using the Kaplan-Meier method with log-rank test, respectively. Multivariate Cox proportional hazards model was performed to determine the factors independently associated with NSCLC prognosis.ResultsBRCA1 rs1799966 minor allele C (TC+CC vs. TT, OR = 0.402, 95% CI = 0.204-0.794, p = 0.008) and MDR1/ABCB1 rs1045642 minor allele A (GA +AA vs. GG, OR = 0.478, 95% CI = 0.244-0.934, p = 0.030) were associated with a better response to chemotherapy in advanced NSCLC patients. Survival analyses indicated that BRCA1 rs1799966 TC+CC genotypes were associated with a decreased risk of death (HR = 0.617, 95% CI = 0.402-0.948, p = 0.028) in advanced NSCLC patients, and the association was still significant after the adjustment for covariates. Multivariate Cox regression analysis showed that ERCC1 rs11615 AA genotype (P = 0.020) and smoking (p = 0.037) were associated with increased risks of death in early stage NSCLC patients after surgery.ConclusionsPolymorphisms of genes in DNA repair pathway and MDR1 could contribute to chemotherapy response and survival of patients with NSCLC.

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Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients.

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Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients.

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