DNA Repair Biomarker for Lung Cancer Risk and its Correlation With Airway Cells Gene Expression (original) (raw)
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Low Integrated DNA Repair Score and Lung Cancer Risk
Cancer Prevention Research, 2014
DNA repair is a prime mechanism for preventing DNA damage, mutation, and cancers. Adopting a functional approach, we examined the association with lung cancer risk of an integrated DNA repair score, measured by a panel of three enzymatic DNA repair activities in peripheral blood mononuclear cells. The panel included assays for AP endonuclease 1 (APE1), 8-oxoguanine DNA glycosylase (OGG1), and methylpurine DNA glycosylase (MPG), all of which repair oxidative DNA damage as part of the base excision repair pathways. A blinded population-based case-control study was conducted with 96 patients with lung cancer and 96 control subjects matched by gender, age (AE1 year), place of residence, and ethnic group (Jews/non-Jews). The three DNA repair activities were measured, and an integrated DNA repair OMA (OGG1, MPG, and APE1) score was calculated for each individual. Conditional logistic regression analysis revealed that individuals in the lowest tertile of the integrated DNA repair OMA score had an increased risk of lung cancer compared with the highest tertile, with OR ¼ 9.7; 95% confidence interval (CI), 3.1-29.8; P < 0.001, or OR ¼ 5.6; 95% CI, 2.1-15.1; P < 0.001 after cross-validation. These results suggest that pending validation, this DNA repair panel of risk factors may be useful for lung cancer risk assessment, assisting prevention and referral to early detection by technologies such as low-dose computed tomography scanning. Cancer Prev Res; 7(4); 398-406. Ó2013 AACR. c 239 U represents 1 SD in the control group. d Tertiles of the control subjects' values. The upper tertile was chosen as the referent. Sevilya et al.
Cancer Research, 2009
In previous studies we reported that key antioxidant and DNA repair genes are regulated differently in normal bronchial epithelial cells (NBEC) of lung cancer cases compared to non-lung cancer controls. In an effort to develop a biomarker for lung cancer risk, we evaluated transcript expression of 14 antioxidant, DNA repair and transcription factor genes in NBEC (HUGO names CAT, CEBPG, E2F1, ERCC4, ERCC5, GPX1, GPX3, GSTM3, GSTP1, GSTT1, GSTZ1, MGST1, SOD1, and XRCC1). A test comprising these 14 genes accurately identified the lung cancer cases in two casecontrol studies. The receiver operating characteristic (ROC) area under the curve (AUC) was 0.82 (95% CI, 0.68 -0.91) for the first case-control set (25 lung cancer cases and 24 controls), and 0.87 (95% CI, 0.73 -0.96) for the second set (18 cases and 22 controls). For each gene comprised by the test, the key difference between cases and controls was altered distribution of transcript expression among cancer cases compared to controls, with more lung cancer cases expressing at both extremes among all genes (K-S test, D=0.0795; P=0.041). A novel statistical approach was used to identify for each gene the lower and upper boundaries of transcript expression that optimally classifies cases and controls. Based on the data presented here, there is increased prevalence of lung cancer diagnosis among individuals that express a threshold number of key antioxidant, DNA repair and transcription factor genes at either very high or very low level in normal airway epithelium.
Cancer Research, 2013
Suboptimal cellular DNA repair capacity (DRC) has been shown to be associated with enhanced cancer risk, but genetic variants affecting the DRC phenotype have not been comprehensively investigated. In this study, with the available DRC phenotype data, we analyzed correlations between the DRC phenotype and genotypes detected by the Illumina 317K platform in 1,774 individuals of European ancestry from a Texas lung cancer genome-wide association study. The discovery phase was followed by a replication in an independent set of 1,374 cases and controls of European ancestry. We applied a generalized linear model with single nucleotide polymorphisms as predictors and DRC (a continuous variable) as the outcome. Covariates of age, sex, pack-years of smoking, DRC assay-related variables, and case-control status of the study participants were adjusted in the model. We validated that reduced DRC was associated with an increased risk of lung cancer in both independent datasets. Several suggestive loci that contributed to the DRC phenotype were defined in ERCC2/XPD, PHACTR2, and DUSP1. In summary, we determined that DRC is an independent risk factor for lung cancer, and we defined several genetic loci contributing to DRC phenotype. Cancer Res; 73(1); 256-64. Ó2012 AACR.
Clinical lung cancer, 2013
Lung cancer is the leading cause of cancer-related mortality. Understanding patient attributes that enhance survival and predict recurrence is necessary to individualize treatment options. Patients (N = 162) were dichotomized into favorable (n = 101) and unfavorable (n = 61) groups based on survival characteristics. Ku86 and poly(ADP-ribose) polymerase (PARP) expression measures were incorporated into the analyses. LR, Kaplan-Meier analysis, and Cox regression were used to investigate intervariable relationships and survival. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess associations. Sex (OR, 0.32; CI-0.14, 0.76), squamous cell carcinoma (SCC) (OR, 0.41; CI-0.17, 0.98), and recurrence (OR, 0.04; CI-0.01, 0.20) confer an unfavorable outcome with area under the receiver operating characteristic curve (Az) = 0.788. Patients with increased tumor grade (OR = 1.84; CI-1.06, 3.19) or increased Ku86 intensity (OR, 2.03; CI-1.08, 3.82) wer...
Genetic variation in the DNA repair genes is predictive of outcome in lung cancer
Human Molecular Genetics, 2007
To assess whether DNA repair gene variants influence the clinical behaviour of lung cancer we examined the impact of a comprehensive panel of 109 non-synonymous single-nucleotide polymorphisms (nsSNPs) in 50 DNA repair genes on overall survival (OS) in 700 lung cancer patients. Fifteen nsSNPs were associated with OS, significantly greater than that expected (P 5 0.04). SNPs associated with prognosis mapped primarily to two repair pathways-nucleotide excision repair (NER): ERCC5 D1104H (P 5 0.004); ERCC6 G399D (P 5 0.023), ERCC6 Q1413R (P 5 0.025), POLE (P 5 0.014) and base excision repair: APEX1 D148E (P 5 0.028); EXO1 E670G (P 5 0.007); POLB P242R (P 5 0.018). An increasing number of variant alleles in EXO1 was associated with a poorer prognosis [hazard ratio (HR) 5 1.24; P 5 0.0009]. A role for variation in NER and BRCA2/FA pathway genes as determinants of OS was provided by an analysis restricted to the 456 patients treated with platinum-based agents. Our data indicate that the pathway-based approach has the potential to generate prognostic markers of clinical outcome.
DNA repair is essential for the maintenance of genetic stability. We undertook sequencing to determine common genetic variants in 70 genes involved in three major repair pathways (base excision repair, nucleotide excision repair and mismatch repair) and in DNA synthesis, and investigated their relationship to lung and head and neck (H-N) cancers. Of the 70 genes examined, 62 were successfully screened (exon coverage .20%) by sequencing exons, parts of introns and flanking regions in 32 DNA samples from healthy Caucasian individuals. The strategy used allowed the detection of almost all variants with a minor allele frequency !5% in the regions sequenced. During single-nucleotide polymorphism (SNP) discovery, 772 sequences were detected in introns or regions flanking the gene and 313 were found in exons (leading to 113 non-synonymous variations) during single-nucleotide polymorphism (SNP) discovery. In total, 695 variants were successfully genotyped in 151 lung cancer cases, 251 H-N cancer cases and 172 hospital controls. Score statistics were used to test differences in haplotype frequencies between cases and controls in an unconditional logistic regression model. To account for multiple testing, we associated to each P-value an estimated proportion of false discoveries. Haplotype analysis revealed potential associations (P , 0.05) between lung cancer and eight genes (MSH3, MLH3, POLK, LIG1, ERCC5, PMS1, POLG2 and RPA3) and between H-N cancer and four genes (PMS1, POLG2, POLR2B and RPA1) with false discovery proportions of 25 and 55%, respectively. The DNA synthesis pathway showed a tendency for more differential SNP allele frequencies between H-N cases and controls than expected by chance (P 5 0.05). These results hint to a few potential candidates for further investigation in larger studies.
Lung cancer risk and genetic polymorphisms in DNA repair pathways: a meta-analysis
Journal of nucleic acids, 2010
Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We conducted a meta-analysis of epidemiologic studies on the association between genetic polymorphisms in both base excision repair and nucleotide excision repair pathways, and lung cancer. We found xeroderma pigmentosum complementation group A (XPA) G23A (odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.61-0.94), 8-oxoguanine DNA glycosylase 1 (OGG1) Ser326Cys (OR = 1.22, 95% CI = 1.02-1.45), and excision repair cross-complementing group 2 (ERCC2) Lys751Gln (OR = 1.27, 95% CI = 1.10-1.46) polymorphisms were associated with lung cancer risk. Considering the data available, it can be conjectured that if there is any risk association between a single SNP and lung cancer, the risk fluctuation will probably be minimal. Advances in the identification of new polymorphisms and in high-throughput genotyping techniques will facilitate the analysis of...