Background: Base excision repair (BER) is a highly conserved essential mechanism for maintaining genome integrity. We examined associations among four well-characterized polymorphisms of BER genes ...(OGG1 Ser326Cys, XRCC1 Arg194Trp, XRCC1 Arg280His, and XRCC1 Arg399Gln) and lung cancer risk. Methods: A total of 2188 patients with lung cancer and 2198 control subjects without lung cancer recruited at 15 centers in six Eastern European countries from February 1998 to October 2002 provided DNA samples for genotype analysis. Genetic polymorphisms were analyzed by the fluorescence 5′ exonuclease and Amplifluor assays. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We estimated the false-positive reporting probability (FPRP) for our results by incorporating a range of prior probabilities that specific polymorphisms are associated with lung cancer risk. All statistical tests were two-sided. Results: The overall odds ratio for lung cancer among those with the OGG1 Cys/Cys genotype compared with those with the OGG1 Ser/Ser genotype was 1.34 (95% CI = 0.95 to 1.88); the association was most prominent for adenocarcinoma risk (OR = 1.66, 95% CI = 1.04 to 2.66). Overall, the XRCC1 polymorphisms were not associated with the risk of lung cancer. However, the XRCC1 Arg194Trp and Arg280His variants were each associated with a reduced risk of lung cancer among subjects in the highest quartile of pack-years of smoking compared with common allele homozygotes (ORs of 0.65 95% CI = 0.46 to 0.93 and 0.56 95% CI = 0.36 to 0.86, respectively). The associations between the OGG1 Cys/Cys genotype and adenocarcinoma risk and between XRCC1 Arg194Trp polymorphism and lung cancer risk among heavy smokers remained robust given prior probabilities of 25% (FPRP = 0.238) and 10% (FPRP = 0.276), respectively. Conclusions: Our results do not support a major independent role of BER gene polymorphisms in lung cancer risk. However, we cannot exclude the possibility that the OGG1 Ser326Cys and XRCC1 Arg194Trp polymorphisms play minor roles in lung carcinogenesis.
Background: Incidence and mortality rates of upper aerodigestive tract cancers in Central Europe are among the highest in
the world and have increased substantially in recent years. This increase is ...likely to be due to patterns of alcohol and tobacco
consumption. Genetic susceptibility to upper aerodigestive tract cancer in relation to such exposures is an important aspect
that should be investigated among populations in this region.
Methods: A multicenter case-control study comprising 811 upper aerodigestive tract cancer cases and 1,083 controls was conducted
in: Bucharest (Romania), Lodz (Poland), Moscow (Russia), Banska Bystrika (Slovakia), and Olomouc and Prague (Czech Republic).
We analyzed six SNPs in three genes related to ethanol metabolism: alcohol dehydrogenase 1B and 1C ( ADH1B, ADH1C ) and aldehyde dehydrogenase 2 ( ALDH2 ).
Results: The ADH1B histidine allele at codon 48 was associated with a decreased risk of upper aerodigestive tract cancer; odds ratios (OR) were
0.36 95% confidence interval (95% CI), 0.17-0.77 for medium/heavy drinkers and 0.57 (95% CI, 0.36-0.91) for never/light
drinkers. Moderately increased risks were observed for the ADH1C 350 Val allele (OR, 1.19; 95% CI, 0.98-1.55) and ADH1C 272 Gln allele (OR, 1.24; 95% CI, 0.98-1.55). Medium/heavy drinkers who were heterozygous or homozygous at ALDH2 nucleotide position 248 were at a significantly increased risk of upper aerodigestive tract cancer (OR, 1.76; 95% CI, 1.13-2.75;
OR, 5.79; 95% CI, 1.49-22.5, respectively), with a significant dose response for carrying variant alleles ( P = 0.0007). Similar results were observed for the ALDH2 +82A>G and ALDH2 −261C>T polymorphisms. When results were analyzed by subsite, strong main effects were observed for squamous cell carcinoma
of the esophagus for all six variants. Among the 30% of the population who were carriers of at least one ALDH2 variant, the attributable fraction among carriers (AF c ) was 24.2% (5.7-38.3%) for all upper aerodigestive tract cancers, increasing to 58.7% (41.2-71.0%) for esophageal cancer.
Among carriers who drank alcohol at least thrice to four times a week, the AF c for having at least one ALDH2 variant was 49% (21.3-66.8%) for all upper aerodigestive tract cancers, increasing to 68.9% (42.9-83.1%) for esophageal cancer.
Conclusions: Polymorphisms in the ADH1B and ALDH2 genes are associated with upper aerodigestive tract cancer in Central European populations and interact substantially with
alcohol consumption. (Cancer Epidemiol Biomarkers Prev 2006;15(4):696–703)
Prospective cohort studies have found that prediagnostic circulating vitamin B6 is inversely associated with both risk of kidney cancer and kidney cancer prognosis. We investigated whether ...circulating concentrations of vitamin B6 at kidney cancer diagnosis are associated with risk of death using a case-cohort study of 630 renal cell carcinoma (RCC) patients. Blood was collected at the time of diagnosis, and vitamin B6 concentrations were quantified using LC-MS/MS. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models. After adjusting for stage, age, and sex, the hazard was 3 times lower among those in the highest compared to the lowest fourth of B6 concentration (HR4vs1 0.33, 95% CI 0.18, 0.60). This inverse association was solely driven by death from RCC (HR4vs1 0.22, 95% CI 0.11, 0.46), and not death from other causes (HR4vs1 0.89, 95% CI 0.35, 2.28, p-interaction = 0.008). These results suggest that circulating vitamin B6 could provide additional prognostic information for kidney cancer patients beyond that afforded by tumour stage.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Leukocyte global DNA methylation levels are currently being considered as biomarkers of cancer susceptibility and have been associated with risk of several cancers. In this study, we aimed to examine ...the association between long interspersed nuclear elements (LINE-1) methylation levels, as a biomarker of global DNA methylation in blood cell DNA, and renal cell cancer risk.
LINE-1 methylation of bisulfite-converted genomic DNA isolated from leukocytes was quantified by pyrosequencing measured in triplicate, and averaged across 4 CpG sites. A total of 328 RCC cases and 654 controls frequency-matched(2∶1) on age(±5years), sex and study center, from a large case-control study conducted in Central and Eastern Europe were evaluated.
LINE-1 methylation levels were significantly higher in RCC cases with a median of 81.97% (interquartile rangeIQR: 80.84-83.47) compared to 81.67% (IQR: 80.35-83.03) among controls (p = 0.003, Wilcoxon). Compared to the lowest LINE-1 methylation quartile(Q1), the adjusted ORs for increasing methylation quartiles were as follows: OR(Q2) = 1.84(1.20-2.81), OR(Q3) = 1.72(1.11-2.65) and OR(Q4) = 2.06(1.34-3.17), with a p-trend = 0.004. The association was stronger among current smokers (p-trend<0.001) than former or never smokers (p-interaction = 0.03). To eliminate the possibility of selection bias among controls, the relationship between LINE-1 methylation and smoking was evaluated and confirmed in a case-only analysis, as well.
Higher levels of LINE-1 methylation appear to be positively associated with RCC risk, particularly among current smokers. Further investigations using both post- and pre-diagnostic genomic DNA is warranted to confirm findings and will be necessary to determine whether the observed differences occur prior to, or as a result of carcinogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that ...subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31–1.72; p = 7.75 × 10−9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression.
•Previous Evidence•As a major participant of Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO), we continued monitoring the progress of genomic and other omics studies of lung cancer through regular communications within the consortium and literature search using the PubMed database. The TRICL-ILCCO is one of the largest international consortium of lung cancer which includes many major ongoing lung cancer case-control and cohort studies with the aim of sharing comparable data. Although GWAS successfully defined many lung cancer-associated genomic loci, the integrative studies of multi-dimensional high throughput “-omics” measurements from tumor tissues and corresponding blood specimens are limited.•Added value of this study•We identified a HIFs-EGFR-HDAC4-TERT network associated with lung adenocarcinoma, and subsequent sequencing of network hub genes identified a new locus within EPAS1 that is associated with lung cancer risk. This locus is in hub gene EPAS1, which is a key member of the HIF family involved in every aspect of cancer development and progression.•Implications of all the available evidence•We developed a network building approach for the integrative analysis of multi-omic datasets. The integration of multi-dimensional high throughput “-omics” measurements from tumor tissues and corresponding blood specimens, together with new systems strategies for diagnostics, enables the identification of cancer biomarkers that will facilitate pre-symptomatic diagnosis, stratification of disease, assessment of disease progression, evaluation of patient response to therapy, and identification of recurrences.
Exposure to tobacco smoke and to mutagenic xenobiotics can cause various types of DNA damage in lung cells, which, if not corrected by DNA repair systems, may lead to deregulation of the cell cycle ...and, ultimately, to cancer. Genetic variation could thus be an important factor in determining susceptibility to tobacco-induced lung cancer with genetic susceptibility playing a larger role in young-onset cases compared with that in the general population. We have therefore studied 102 single-nucleotide polymorphisms (SNP) in 34 key DNA repair and cell cycle control genes in 299 lung cancer cases diagnosed before the age of 50 years and 317 controls from six countries of Central and Eastern Europe. We have found no association of lung cancer risk with polymorphisms in genes related to cell cycle control, single-strand/double-strand break repair, or base excision repair. Significant associations (P < 0.05) were found with polymorphisms in genes involved in DNA damage sensing (ATM) and, interestingly, in four genes encoding proteins involved in mismatch repair (LIG1, LIG3, MLH1, and MSH6). The strongest associations were observed with heterozygote carriers of LIG1 -7C>T odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.13-2.64 and homozygote carriers of LIG3 rs1052536 (OR, 2.05; 95% CI, 1.25-3.38). Consideration of the relatively large number of markers assessed diminishes the significance of these findings; thus, these SNPs should be considered promising candidates for further investigation in other independent populations.
Although active tobacco smoking has been identified as a major risk factor for head and neck cancer, involuntary smoking has
not been adequately evaluated because of the relatively low statistical ...power in previous studies. We took advantage of data
pooled in the International Head and Neck Cancer Epidemiology Consortium to evaluate the role of involuntary smoking in head
and neck carcinogenesis. Involuntary smoking exposure data were pooled across six case-control studies in Central Europe,
Latin America, and the United States. Adjusted odds ratios (OR) and 95% confidence interval (95% CI) were estimated for 542
cases and 2,197 controls who reported never using tobacco, and the heterogeneity among the study-specific ORs was assessed.
In addition, stratified analyses were done by subsite. No effect of ever involuntary smoking exposure either at home or at
work was observed for head and neck cancer overall. However, long duration of involuntary smoking exposure at home and at
work was associated with an increased risk (OR for >15 years at home, 1.60; 95% CI, 1.12-2.28; P trend < 0.01; OR for >15 years at work, 1.55; 95% CI, 1.04-2.30; P trend = 0.13). The effect of duration of involuntary smoking exposure at home was stronger for pharyngeal and laryngeal cancers
than for other subsites. An association between involuntary smoking exposure and the risk of head and neck cancer, particularly
pharyngeal and laryngeal cancers, was observed for long duration of exposure. These results are consistent with those for
active smoking and suggest that elimination of involuntary smoking exposure might reduce head and neck cancer risk among never
smokers. (Cancer Epidemiol Biomarkers Prev 2008;17(8):1974–81)
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