Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer

To test the hypothesis that genetic variation in the metabolism of tobacco carcinogens, such as aromatic amines (AA) and heterocyclic amines (HCA), contributes to pancreatic cancer, we have examined genetic polymorphisms of three key enzymes, i.e. cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 and 2 (NAT1 and NAT2), in a hospital-based case-control study of 365 patients with pancreatic adenocarcinoma and 379 frequency-matched healthy controls. Genotypes were determined using PCR-restriction fragment length polymorphism (RFLP) and Taqman methods. Smoking information was collected by personal interview. Adjusted odds ratio (AOR) and 95% confidence interval (CI) was estimated by unconditional multivariate logistic regression analysis. We found that the NAT1 'rapid' alleles were associated with a 1.5-fold increased risk of pancreatic cancer (95% CI: 1.0-2.1) with adjustment of potential confounders. This effect was more prominent among never smokers (AOR: 2.4, 95% CI: 1.4-4.3) and females (AOR: 1.8, 95% CI: 1.0-3.1). Some genotypes were significantly associated with increased risk for pancreatic cancer among smokers, especially heavy smokers (<20 pack years). For example, heavy smokers with the CYP1A2*1D (T-2467delT) delT, CYP1A2*1F(A-163C) C allele, NAT1 'rapid' or NAT2 'slow' alleles had an AOR (95% CI) of 1.4 (0.7-2.3), 1.9 (1.1-3.4), 3.0 (1.6-5.4) and 1.5 (0.8-2.6), respectively, compared with never smokers carrying the non-at-risk alleles. These effects were more prominent in females than in males. The corresponding AOR (95% CI) was 3.1 (1.0-8.0), 3.8 (1.5-10.1), 4.5 (1.6-12.7) and 2.0 (0.8-5.1) for females versus 1.0 (0.4-1.9), 1.1 (0.5-2.4), 2.1 (1.0-4.6) and 1.1 (0.5-2.6) for males. A significant synergistic effect of CYP1A2*1F C allele and NAT1"rapid" alleles on the risk for pancreatic cancer was also detected among never smokers (AOR: 2.9, 95% CI: 1.2-6.9) and among females (AOR: 2.5, 95% CI: 1.1-5.7). These data suggest that polymorphisms of the CYP1A2 and NAT1 genes modify the risk of pancreatic cancer.     

Passive smoking and the use of noncigarette tobacco products in association with risk for pancreatic cancer: a case-control study

BACKGROUND: The associations between passive smoking and the use of noncigarette tobacco products with pancreatic cancer are not clear. METHODS: In this case-control study, the authors collected information on passive smoking and the use of noncigarette tobacco products in 808 patients with pancreatic adenocarcinoma and 808 healthy controls by personal interview. Multivariable logistic regression was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (95% CI). RESULTS: The results confirmed the previously reported association between active smoking and increased risk for pancreatic cancer. The AOR was 1.7 (95% CI, 1.4-2.2) for regular smokers, 1.8 (95% CI, 1.4-2.4) for long-term smokers, and 3.1 (95% CI, 2.2-4.3) for former smokers. Although passive smoking showed a nonsignificantly elevated risk for pancreatic cancer in the entire study population (AOR, 1.3; 95% CI, 0.9-1.7), the association was present among ever smokers (AOR, 1.7; 95% CI, 1.03-2.6) but was absent among never smokers (AOR, 1.1; 95% CI, 0.8-1.6). Neither intensity nor duration of passive smoking modified the risk of pancreatic cancer among never smokers. The use of chewing tobacco, snuff, and pipes showed no significant risk elevation for pancreatic cancer after controlling for the confounding effects of demographics and other known risk factors. The use of cigars in never smokers showed a borderline significant increase of risk for pancreatic cancer (AOR, 2.2; 95% CI, 1.0-4.7; P = .05). CONCLUSIONS: The current observations did not support a role for passive smoking or the use of noncigarette tobacco products in the etiology of pancreatic cancer. The association between cigar use and the risk of pancreatic cancer needs to be confirmed in other study populations.     

Lack of Associations between Genetic Polymorphisms in GSTM1, GSTT1 and GSTP1 and Pancreatic Cancer Risk: A Multi-Institutional Case-Control Study in Japan

Background: We aimed to evaluate the role of genetic polymorphisms in tobacco carcinogen-metabolizinggenes and their interactions with smoking in a hospital-based case-control study of Japanese subjects. Materialsand Methods: We examine the associations of pancreatic cancer risk with genetic polymorphisms in GSTM1,GSTT1 and GSTP1, phase II enzymes that catalyze the conjugation of toxic and carcinogenic electrophilicmolecules. The study population consisted of 360 patients and 400 control subjects, who were recruited fromseveral medical facilities in Japan. Unconditional logistic regression methods were used to estimate odds ratios(ORs) and 95% confidence intervals (CIs) for the associations between genotypes and pancreatic cancer risk.Results: Among the control subjects, the prevalence of the GSTM1-null genotype and the GSTT1-null genotypewas approximately 56% and 48%, respectively. Cases and controls were comparable in terms of GSTM1 andGSTT1 genotype distributions. Neither of the deleted polymorphisms in GSTM1 and GSTT1 was associated withthe risk of pancreatic cancer, with an age- and sex-adjusted OR of 0.99 (95%CI: 0.74-1.32) for the GSTM1-nullgenotype, and 0.98 (95%CI: 0.73-1.31) for the GSTT1-null genotype. The OR was 0.97 (95%CI: 0.64-1.47) forindividuals with the GSTM1 and GSTT1-null genotypes compared with those with the GSTM1 and GSTT1-present genotypes. No synergistic effects of smoking or GST genotypes were observed. Conclusions: Our resultsindicate no overall association between the GSTM1 and GSTT1 deletion polymorphisms and pancreatic cancerrisk in the Japanese subjects in our study.     

Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer

The MMPs (matrix metalloproteinases) are a family of secreted zinc metalloproteases that degrade the collagens of the extracellular matrix important in tissue remodeling and repair during development and inflammation. We investigated the associations between polymorphisms of MMP-1 (-1607 1G/2G, rs1799750), MMP-3 (-1171 5A/6A, rs3025058), and MMP-12 (-82AG, rs2276109, and 1082A/G, rs652438) and the risk of lung cancer in 2014 Caucasian lung cancer patients and 1323 healthy controls. The results were analyzed using logistic regression models, adjusting for covariates. The four polymorphisms were in Hardy-Weinberg disequilibrium. Except for the 1G-1082A, the other linkage disequilibrium tests between the four MMP polymorphisms were statistically significant (P < 0.001). There was no overall association between individual MMP polymorphism and the risk of lung cancer. The MMP polymorphisms jointly were associated with a non-statistically significant higher risk of lung cancer, with the adjusted odds ratio (AOR) of subjects with 5+ variant alleles versus zero variant allele of 1.31 [95% confidence interval (CI), 0.92-1.88]. Stronger associations were observed in never-smokers and males, with the corresponding AORs of 2.44 (95%CI, 1.10-5.43, P(trend) = 0.04) in never smokers and 1.35 (95%CI, 0.79-2.30, P(trend) = 0.04) in men. In haplotype analysis, the 1G-6A-82A-1082G haplotype was associated with higher risk of lung cancer among never smokers, with the AOR of 3.65 (95%CI, 1.62-8.20) when compared with the most common 1G-5A-82A-1082A haplotype. In conclusion, the combined MMP genotypes and associated haplotypes may be associated with higher risk of lung cancer, particularly among never smokers and men.     

Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk

GSTP1 and GSTM1 are genes involved in Phase II metabolism, whereas p53 is a tumor suppressor gene. Individually, functional polymorphisms of these genes have been studied as risk factors for lung cancer. Small sample sizes have hindered the detection of possible increases in risk associated with having two or more "at risk" polymorphisms of these three genes. In a large Caucasian population, we examined the association of combined variant genotypes [or double-variants (DVs)] of these three genes and lung cancer risk, compared with their corresponding "double-wild-type" genotypes. Because these DVs may promote lung carcinogenesis at an earlier age, a subgroup of individuals aged 55 years or younger was examined separately. Using a case-control design, individuals were genotyped for GSTM1, GSTP1, and p53 codon 72 using PCR-RFLP techniques. All of the analyses used multiple logistic regression. Indicator variables were created to evaluate the risk for individuals with the following DVs: GSTP1 GG + GSTM1-null and GSTP1 GG + p53 Arg/Pro or Pro/Pro. A total of 1694 cases and controls were evaluated. In the whole population, those with the double variants have a higher risk of lung cancer when compared with those with the double-wild-type genotypes, supporting our original hypothesis. Individuals with the GSTP1 and GSTM1, DV (P1-M1 DV) had a marginally significant higher risk of lung cancer compared with their double-wild-type counterparts [adjusted odds ratio (AOR), 1.60; 95% confidence interval (CI), 0.95-2.70]. A significantly higher risk was found for the GSTP1, p53 DV (P1-p53 DV; AOR, 1.99; 95% CI, 1.12-3.53). Among individuals aged 55 or younger, these risks were even higher: for the P1-M1 DV the AOR was 4.03 (95% CI, 1.47-11.1); for the P1-p53 DV the AOR was 5.10 (95% CI, 1.42-18.30). Specific DVs of GSTM1, GSTP1, and p53 codon 72 are associated with a higher lung cancer risk. This susceptibility is highest among younger individuals.     

Association between self-reported environmental tobacco smoke exposure and lung cancer: modification by GSTP1 polymorphism

Environmental Tobacco Smoke (ETS) exposure has been associated with lung cancer risk. ETS is composed of emissions from cigarette smoke and contains a higher concentration of tobacco smoke carcinogens than mainstream smoke. Polymorphisms in genes that metabolize tobacco smoke carcinogens have been studied as effect modifiers of the association between active smoking and lung cancer risk. GSTP1 is a polymorphic gene that encodes for GST pi, a detoxification enzyme and has a high expression in the lung. We investigated the association between ETS and lung cancer risk and the modification of this association by the GSTP1 polymorphism. Using a case-control design, individuals were genotyped for GSTP1 using PCR-RFLP techniques. All analyses were carried out using multiple logistic regression. The association between ETS exposure and lung cancer risk was evaluated in different strata based on smoking habits to evaluate the consistency of results. The effect of the GSTP1 polymorphisms on lung cancer risk was evaluated by considering the joint effect of having both an ETS exposure and the GSTP1 GG genotype compared to the absence of ETS exposure and the GSTP1 AA genotype as a reference group as well as doing stratified analysis by genotype. ETS exposure was associated consistently with higher lung cancer risk in all the strata considered. The adjusted odds ratios (AOR) evaluating the association between ETS and lung cancer risk for the different strata were: nonsmokers (Cases/Controls 66/413; AOR = 1.38; 95% CI = 0.78-2.43), ex-smokers (Cases/Controls 560/527; AOR = 1.66; 95% CI = 1.22-2.25), current smokers (Cases/Controls 415/219; AOR = 1.56; 95% CI = 1.00-2.41). The AORs for ex-smokers and light smoking subgroups were: ex-smokers who quit for 19 years or more (Cases/Controls 144/244; AOR = 2.64; 95% CI = 1.55-4.50), ex-smokers who quit for 10-19 years (Cases/Controls 141/128; AOR = 1.16; 95% CI = 0.66-2.04), ex-smokers who quit for 10 years or less (Cases/Controls 247/122; AOR = 1.45; 95% CI = 0.83-2.55) and participants who had <15 packyears and nonsmokers combined (Cases/Controls 143/640; AOR = 1.52; 95% CI = 1.02-2.28). Among those with the GSTP1 GG genotype the ETS-lung cancer risk association was greater than those with the GSTP1 AA genotype: nonsmokers (GSTP1 GG AOR = 7.84; 95% CI = 0.80-76.68; GSTP1 AA AOR = 1.15; 95% CI = 0.46-2.90), ex-smokers (GSTP1 GG AOR = 2.32; 95% CI = 0.90-5.96; GSTP1 AA AOR = 2.15; 95% CI = 1.34-3.44), current smokers (GSTP1 GG AOR = 1.75; 95% CI = 0.42-7.32; GSTP1 AA AOR = 1.32; 95% CI = 0.67-2.58) and participants who had <15 packyears and nonsmokers (GSTP1 GG AOR = 1.93; 95% CI = 0.54-6.97; GSTP1 AA AOR = 1.58; 95% CI = 0.83-3.01). We found that ETS exposure is associated with higher lung cancer risk. Furthermore, the presence of the GSTP1 GG genotype appears to enhance the magnitude of the association between ETS exposure and lung cancer. Larger studies will be needed to confirm these preliminary findings.     

Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer.

Cigarette smoking may induce DNA damage. Lower DNA repair capacities have been associated with higher risk of lung cancer. Excision repair cross-complementing group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process, and low expression of ERCC1 mRNA levels has been associated with higher risk of cancers. We examined the association between two polymorphisms of ERCC1, 8092C > A (rs3212986) and 19007T > C (codon 118, rs11615), which are associated with altered ERCC1 mRNA stability and mRNA levels, in 1,752 Caucasian lung cancer patients and 1,358 controls. The results were analyzed using logistic regression models, adjusting for relevant covariates. The two polymorphisms were in Hardy-Weinberg disequilibrium and in linkage disequilibrium. There was no overall association between ERCC1 polymorphisms and lung cancer risk, with the adjusted odds ratios (AOR) of 1.26 [95% confidence interval (95% CI), 0.81-1.96] for the 8092C > A polymorphism (A/A versus C/C) and 0.93 (95% CI, 0.67-1.30) for the 19007T > C polymorphism (C/C versus T/T). Stratified analyses revealed that the AORs for the 8092C > A polymorphism (A/A versus C/C) decreased significantly as pack-years increased, with the AOR of 2.11 (95% CI, 1.03-4.31) in never smokers and 0.50 (95% CI, 0.25-1.01) in heavy smokers (>/=56 pack-years), respectively. Consistent results were found when gene-smoking interaction was incorporated by joint effects and interactions models that considered both discrete and continuous variables for cumulative smoking exposure. The same direction for the gene-smoking interaction was found for the 19007T > C polymorphism, although the interaction was not statistically significant. In conclusion, ERCC1 8092C > A polymorphism may modify the associations between cumulative cigarette smoking and lung cancer risk.     

Polymorphisms of SPINK1 N34S and CFTR in patients with sporadic and familial pancreatic cancer

Long standing chronic pancreatitis is a risk factor for developing pancreatic cancer. Inheritance of polymorphisms in SPINK1 and CFTR are associated with an increased risk of developing pancreatitis. The aim of this study was to determine if patients who carry polymorphisms in SPINK1 and CFTR are at increased risk of developing pancreatic cancer through the development of chronic pancreatitis. DNA from patients with histologically-confirmed surgically-treated chronic pancreatitis, familial and sporadic pancreatic adenocarcinoma and controls were analyzed for the N34S polymorphism of SPINK1 and the two commonest polymorphisms of the CFTR gene, the DF508 mutation and the 5T polymorphism. These polymorphisms were determined using restriction fragment length polymorphism, PCR and cycle sequencing methods. The SPINK1 N34S polymorphism was detected in 5 of 172 (2.9%) patients with chronic pancreatitis, in 4 of 200 (2.0%) patients with sporadic pancreatic adenocarcinoma, in 0 of 36 (0%) of patients with familial pancreatic cancer and in 3 of 177 (1.7%) controls of chronic cholecystitis. The CFTR 5T polymorphism was identified in 31 of 334 (9.3%) patients of sporadic pancreatic cancer, in 5 of 43 (11.6%) patients with familial pancreatic cancer and in 10 of 112 (8.9%) controls with colorectal cancer. The CFTR DF508 mutation was recognized in 6 of the 240 (2.5%) patients with pancreatic adenocarcinoma, a prevalence similar to that of control populations. We conclude that the N34S polymorphism of SPINK1 and the 5T and DF508 CFTR polymorphisms do not predispose to the development of pancreatic adenocarcinoma. Furthermore, the N34S polymorphism is rarely found in patients with severe idiopathic chronic pancreatitis.     

Gene-environment interaction: the role of SULT1A1 and CYP3A5 polymorphisms as risk modifiers for squamous cell carcinoma of the oesophagus

An imbalance in the activities of enzymes involved in the metabolism, conjugation and transport of xenobiotics may account for the variability in susceptibility to the development of complex diseases such as cancer between different population groups. In this study we investigated a functional polymorphism in the SULT1A1 gene in 245 patients and 288 controls. Previous studies have shown that the 638G-->A polymorphism that results in the substitution of arginine by histidine at codon 213 (SULT1A1*2) results in decreased SULT1A1 activity. The same group of samples used in this study had been previously genotyped for CYP3A5 genetic polymorphisms. Among Black subjects the burning of wood or charcoal for cooking and keeping warm was significantly associated with increased risk for oesophageal cancer (OC) (AOR, 15.2; P=0.001) as was the consumption of home-brewed beer (AOR, 6.97; P=0.0001). Among the Mixed Ancestry group, tobacco smoking combined with alcohol consumption were significantly associated with higher risk for OC (AOR, 5.18; P=0.0005). In both Blacks and Mixed Ancestry subjects, starting to smoke below the age of 20 years was associated with significantly increased risk for OC (AOR, 3.5 among the Blacks and AOR, 12 among the Mixed Ancestry). The homozygous SULT1A1*2/*2 genotype was associated with increased risk for OC among smokers. The SULT1A1*2/*2 genotype in combination with the CYP3A5 heterozygous genotypes was associated with significantly increased risk for OC (AOR, 3.60; P=0.001) with the risk being even higher among smokers compared with non-smokers. The above findings confirm the association between alcohol consumption and tobacco smoking with increased risk for OC. The genotype results show that SULT1A1*2/*2 genotype is associated with increased risk for OC among subjects exposed to tobacco-smoke-related carcinogens.     

Associations of GSTM1 and GSTT1 polymorphisms with pancreatic cancer risk

Glutathione S-transferases (GSTs), including glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1), are multifunctional enzymes which play vital roles in the detoxification of a variety of carcinogens. The genetic polymorphisms of GSTM1 and GSTT1 have been implicated in pancreatic cancer risk, but the results of published studies remain conflicting. Thus, a meta-analysis was conducted to estimate the effect of GSTM1 and GSTT1 polymorphisms on the risk of developing pancreatic cancer. A comprehensive search was performed in the PubMed, Embase, Web of Science, and Wanfang databases to identify the available studies on the associations of GSTM1 and GSTT1 polymorphisms with pancreatic cancer risk. The pooled odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI) was used to estimate the associations. Stratified analyses by ethnicity and sensitivity analyses were performed to further identify the relationships. Overall, the null genotype of GSTT1 was associated with an increased risk of pancreatic cancer (OR?=?1.61, 95 % CI 1.06–2.44, P _OR?=?0.025), but similar association was not found between the null genotype of GSTM1 and pancreatic cancer risk. Besides, a significant association of GSTT1 polymorphism with pancreatic cancer risk was identified in Asians (OR?=?2.58, 95 % CI 1.67–3.98, P _OR?<?0.001), but not in Caucasians (OR?=?1.16, 95 % CI 0.94–1.43, P _OR?=?0.170). Sensitivity analyses by sequential omission of individual study confirmed the stability of our results. Meta-analysis of available data thus far shows that the null genotype of GSTT1 is a risk factor for pancreatic cancer, particularly in the Asian population. The currently available data are not sufficient enough to identify the association between the GSTM1 polymorphism and pancreatic cancer risk.     

MTHFR Gene Polymorphisms are Not Involved in Pancreatic Cancer Risk: A Meta-analysis

Purpose: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to beassociated with pancreatic cancer, but the published studies have yielded inconsistent results. This study assessedthe relationship between MTHFR gene polymorphisms and the risk for pancreatic cancer using a meta-analysisapproach. Methods:A search of Google scholar, PubMed, Cochrane Library and CNKI databases before April 2012was performed, and then associations of the MTHFR polymorphisms with pancreatic cancer risk were summarized.The association was assessed by odds ratios (ORs) with 95% confidence intervals (CIs). Publication bias was alsocalculated. Results: Four relative studies on MTHFR gene polymorphisms (C667T and A1298C) were included inthis meta-analysis. Overall, C667T (TT vs. CC:OR=1.61,95%CI=0.78-3.34; TT vs. CT: OR=1.41,95%CI=0.88-2.25;Dominant model:OR=0.68,95%CI=0.40-1.17; Recessive model: OR=0.82,95%CI=0.52-1.30) and A1298C (CCvs. AA:OR=1.01,95%CI=0.47-2.17; CC vs. AC: OR=0.99,95%CI=0.46-2.14; Dominant model:OR=1.01,95%CI=0.47-2.20; Recessive model: OR=1.01,95%CI=0.80-1.26) did not increase pancreatic cancer risk.Conclusions: This meta-analysis indicated that MTHFR polymorphisms (C667T and A1298C) are not associatedwith pancreatic cancer risk.     

Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma

BACKGROUND: Pancreatic cancer risk has been linked to chronic pancreatitis and periodontitis, suggesting a role for inflammation in disease etiology. Myeloperoxidase (MPO) and superoxide dismutase (SOD2) are enzymes that regulate reactive oxygen species and contain recognized single nucleotide polymorphisms (SNPs) that confer altered enzyme activity. METHODS: One hundred twenty-two patients with pancreatic cancer and 331 age- and sex-matched controls were analyzed for polymorphisms of the MPO - guanine 463 adenine (-G463A) and the SOD2 alanine (Ala)-to-valine (Val) polymorphism at codon 16 (Ala16Val) genes. Cases and controls were analyzed for associations between these polymorphisms, adjusting for sex, age, history of alcohol use and smoking history. RESULTS: The variant A allele of MPO -G463A was associated with a lower risk of pancreatic cancer (adjusted odds ratio [OR] for pancreatic cancer, 0.57; 95% confidence interval [95% CI], 0.4-0.9; P = .02). The SOD2 homozygous variant genotype (Val/Val) was associated with a greater risk of pancreatic cancer (adjusted OR, 1.96; 95% CI, 1.0-3.8; P = .04). Compared with individuals who carried both low-risk alleles (A/- and Ala/-), significantly more cases than controls carried both high-risk genotypes (G/G and Val/Val; adjusted OR, 4.31; 95% CI, 1.8-10; P = .001), or 1 high-risk genotype (adjusted OR, 1.96; 95% CI, 1.1-3.4; P = .01). CONCLUSIONS: Polymorphisms of the inflammatory pathway genes MPO -G463A and SOD2 Ala16Val are associated with elevated pancreatic cancer risk. Oxidative stress may play an important role in pancreatic cancer carcinogenesis.     

Association between polymorphisms in UDP-glucuronosyltransferase 1A6 and 1A7 and colorectal cancer risk

Genetic polymorphisms of uridine diphosphate-glucuronosyltransferases 1A6 (UGT1A6) and 1A7 (UGT1A7) may lead to genetic instability and colorectal cancer carcinogenesis. Our objective was to measure the interaction between polymorphisms of these repair genes and tobacco smoking in colorectal cancer (CRC). A total of 68 individuals with CRC and 112 non-cancer controls were divided into non-smoker and smoker groups according to pack-years of smoking. Genetic polymorphisms of UGT1A6 and UGT1A7 were examined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We found a weak association of UGT1A6 polymorphisms with CRC risk (crude odds ratio [OR], 1.65; 95% confidence interval [95%CI], 0.9-3.1, P=0.107; adjusted OR 1.95, 95%CI 1.0-3.8, P=0.051). The ORs for the UGT1A7 polymorphisms were statistically significant (crude OR: 26.40, 95%CI: 3.5-198.4, P=0.001; adjusted OR: 21.52, 95%CI: 2.8-164.1, P=0.003). The joint effect of tobacco exposure and UGT1A6 polymorphisms was significantly associated with colorectal cancer risk in non-smokers (crude OR, 2.11; 95%CI, 0.9-5.0, P=0.092; adjusted OR 2.63, 95%CI 1.0-6.7, P=0.042). In conclusion, our findings suggest that UGT1A6 and UGT1A7 gene polymorphisms are associated with CRC risk in the Japanese population. In particular, UGT1A6 polymorphisms may strongly increase CRC risk through the formation of carcinogens not associated with smoking.     

A population-based, case-control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk

BACKGROUND: Cigarette smoking is associated with a twofold increased risk of pancreatic cancer. We conducted a population-based case-control study in six San Francisco Bay area counties from 1994 to 2001 to investigate associations between polymorphisms in genes for two carcinogen-metabolizing enzymes (cytochrome P450 1A1 [CYP1A1] and glutathione S-transferase [GST]), smoking, and adenocarcinoma of the exocrine pancreas. METHODS: We used polymerase chain reaction-based methods to analyze blood samples obtained from 309 case subjects and 964 control subjects to determine their genotypes for three CYP1A1 polymorphisms (m1, m2, and m4) and for homozygous deletions of two GST genes, GSTM1 and GSTT1. Control subjects were frequency matched to case subjects by age and sex. All statistical tests were two-sided. RESULTS: None of the genetic polymorphisms themselves affected the risk of pancreatic cancer among Caucasian study participants. However, we observed an interaction between GSTT1-null genotype and cigarette smoking among Caucasians that was more prominent among women than among men. Relative to never smokers with the GSTT1-present genotype, the age-adjusted odds ratios (ORs) of pancreatic cancer for heavy smokers with the GSTT1-null genotype were 5.0 (95% confidence interval [CI] = 1.8 to 14.5) for women and 3.2 (95% CI = 1.3 to 8.1) for men; for heavy smokers with the GSTT1-present genotype they were 2.0 (95% CI = 1.0 to 4.0) for women and 2.1 (95% CI = 1.1 to 3.9) for men. ORs for pancreatic cancer among heavy smokers with both GSTT1-null and GSTM1-null genotypes were similar in magnitude to those among heavy smokers with the GSTT1-null genotype alone. There was no evidence of an interaction between CYP1A1 polymorphisms and smoking. CONCLUSIONS: The combination of heavy smoking and a deletion polymorphism in GSTT1 is associated with an increased risk of pancreatic cancer among Caucasians, with the associations possibly stronger in women than in men.     

The relationship between new-onset diabetes mellitus and pancreatic cancer risk: A case-control study

Diabetes mellitus (DM) is widely considered to be associated with pancreatic cancer, however, whether DM is a cause or consequence of pancreatic cancer is controversial. In the present study, 1458 patients with pancreatic ductal adenocarcinoma (PDAC) and 1528 age-, sex- and sociodemographic variables-matched controls were recruited in two university-affiliated hospitals from 1st January 2000 to 31st December 2009. DM was defined as fasting blood glucose (FBG) level of 7.0 mmol/L or greater. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs) and 95% confidence interval (CI). Compared with controls, a moderate increased risk of PDAC was observed among cases with long-standing diabetes (?2-year duration), with an AOR (95% CI) of 2.11 (1.51-2.94). Interestingly, a significant higher risk was observed among cases with new-onset DM (<2-year duration), with an AOR of 4.43 (3.44-5.72) compared to controls without DM. In addition, we found a synergistic interaction between cigarette smoking and DM on modifying the risk of pancreatic cancer development (AOR = 6.17, 95% CI 3.82-9.94). Similarly, a synergistic interaction between new-onset DM and family history of pancreatic cancer was found for pancreatic cancer risk, with an AOR (95% CI) of 11.04 (2.51-48.53). This study suggested that DM could be both an early manifestation of pancreatic cancer and an aetiologic factor. Possible effect modification on DM by family history of pancreatic cancer and smoking status should be further explored in future aetiologic studies.     

Genetic polymorphisms of interleukin 1&beta; gene and sporadic pancreatic neuroendocrine tumors susceptibility

AIM: To evaluate the association between the interleukin 1β (IL-1β) polymorphisms and the pancreatic neuroendocrine tumor (pNET) development. METHODS: A case-control study was conducted analyzing IL-1β polymorphisms using germline DNA collected in a population-based case-control study of pancreatic cancer (51 pNET cases, 85 pancreatic ductal adenocarcinoma cases, 19 intraductal papillary mucinous neoplasm and 98 healthy controls). RESULTS: The distribution of genotypes for the -511 C/T polymorphism in the pNET patient groups showed significant difference compared to the control group. It is known that the carriers of the IL-1β -511T allele have increased concentrations of IL-1β. The -511 CT and TT high-expression genotypes were over-represented in pNET patients. CONCLUSION: The findings of this study suggested a possible role of IL-1β -511 C/T genotypes in the pathogenesis of pNETs since the presence of the IL-1β -511 CT and TT genotypes and the T allele was associated with an increased risk of pNET only.     

GSTM1, GSTT1 and CYP1A1 Polymorphisms and Risk of Oral Cancer: a Case-control Study in Jakarta,Indonesia

Purpose: to investigate genetic polymorphisms in GSTM1, GSTT1 and CYP1A1 and the association withthe risk of oral cancer in the Jakarta population. Method: A total of 81 cases and 162 controls matched for ageand sex were selected from 5 hospitals in Jakarta. Sociodemographic data using questionnaires were obtainedand peripheral blood samples were collected with informed consent for PCR-RFLP assay. Conditional logisticregression analysis was performed to obtain the association between the risk of oral cancer and GSTM1, GSTT1and CYP1A1 polymorphisms. Results: GSTM1 and GSTT1 null were slightly overrepresented among cases(60.5% and 45.7% respectively) compared to controls (55.6% and 41.4% respectively), but no statisticallysignificant differences were observed. In contrast, the distribution of CYP1A1 polymorphism was higher amongcontrols compared to cases (52.5 % versus 42.4 %). The odds ratio of null GSTM1 and GSTT1 genotypes wasslightly higher compared to wild type genotypes (OR 1.19, 95% CI 0.70-2.02 and OR 1.19, 95% CI 0.72-2.05respectively). Furthermore, the presence of CYP1A1 polymorphism did not increase the risk of oral cancer (OR0.70, 95% 0.39-1.25). Conclusion: Genetic polymorphisms of GSTM1, GSTT1 and CYP1A1 may not be riskfactors for oral cancer in the Jakarta population.     

MTHFR polymorphisms and pancreatic cancer risk: lack of evidence from a meta-analysis

Objective: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported tobe associated with pancreatic cancer, but the published studies had yielded inconsistent results.We thereforeperformed the present meta-analysis. Methods: A search of Google scholar, PubMed, Cochrane Library andCNKI databases before April 2012 was conducted to summarize associations of MTHFR polymorphisms withpancreatic cancer risk. Assessment was with odds ratios (ORs) and 95% confidence intervals (CIs). Publicationbias were also calculated. Results: Four relative studies on MTHFR gene polymorphisms (C667T and A1298C)were involved in this meta-analysis. Overall, C667T(TT vs. CC : OR = 1.61, 95%CI = 0.78 - 3.34; TT vs. CT :OR = 1.41, 95%CI = 0.88-2.25; dominant model: OR = 0.68, 95%CI = 0.40-1.17; recessive model: OR = 0.82,95%CI = 0.52-1.30) and A1298C(CC vs. AA:OR=1.01, 95%CI=0.47-2.17; CC vs. AC: OR=0.99,95%CI=0.46-2.14;dominant model: OR=1.01, 95%CI = 0.47-2.20; recessive model: OR = 1.01, 95%CI = 0.80-1.26) did not increasepancreatic cancer risk. Conclusion: This meta-analysis indicated that MTHFR polymorphisms (C667T andA1298C) were not associated with pancreatic cancer risk.     

Genetic Polymorphisms of the Human Cytochrome P450 1A1 (CYP1A1) and Cervical Cancer Susceptibility among Northeast Thai Women

Background: CYP1A1 is an enzyme in phase I of the cytochrome P450 (CYP) superfamily, and plays a key role in detoxification of carcinogens. Host genetic predisposition in the CYP1A1 may be associated with an increased susceptibility to cervical cancer.The study aimed to evaluate four common polymorphisms of the CYP1A1 and cervical cancer susceptibility among Northeast Thai women. Methods: A case-control study was conducted involving 204 patients with squamous cell cervical cancer (SCCA) and 204 age-matched healthy controls. DNA was extracted from peripheral blood leucocytes. CYP1A1 m1, m3, and m4 genotypes were detected using PCR-RFLP, whereas the CYP1A1 m2 genotype was investigated using real-time PCR. Haplotype analysis was performed using PHASE algorithm version 2.1.1. Results: CYP1A1 m3 was monomorphic. Association between the common CYP1A1 polymorphisms, m1 and m2, and cervical cancer risk was not observed (p>0.05), nor was any association found between the m1–m2–m4 haplotype and cervical cancer risk (p>0.05). Interestingly, the CA genotype of CYP1A1 m4 was observed in 30.88% of the cervical cancer patients but was absent in healthy controls. Conclusion: Our results demonstrated a possible involvement of the CYP1A1 m4 polymorphism but no other common polymorphisms (viz., m1, m2, and m3) in the risk for cervical cancer.This finding may be useful when screening for risk of cervical cancer among Northeast Thai women.     

Risk of cancer in long-term levothyroxine users: Retrospective population-based study

Levothyroxine is a widely prescribed medication for the treatment of an underactive thyroid. The relationship between levothyroxine use and cancer risk is largely underdetermined. To investigate the magnitude of the possible association between levothyroxine use and cancer risk, this retrospective case-control study was conducted using Taiwan’s Health and Welfare Data Science Center database. Cases were defined as all patients who were aged ≥20 years and had a first-time diagnosis for cancer at any site for the period between 2001 and 2011. Multivariable conditional logistic regression models were used to calculate an adjusted odds ratio (AOR) to reduce potential confounding factors. A total of 601 733 cases and 2 406 932 controls were included in the current study. Levothyroxine users showed a 50% higher risk of cancer at any site (AOR: 1.50, 95% CI: 1.46-1.54; P < .0001) compared with non–users. Significant increased risks were also observed for brain cancer (AOR: 1.90, 95% CI: 1.48-2.44; P < .0001), skin cancer (AOR: 1.42, 95% CI: 1.17-1.72; P < .0001), pancreatic cancer (AOR: 1.27, 95% CI: 1.01-1.60; P = .03), and female breast cancer (AOR: 1.24, 95% CI: 1.15-1.33; P < .0001). Our study results showed that levothyroxine use was significantly associated with an increased risk of cancer, particularly brain, skin, pancreatic, and female breast cancers. Levothyroxine remains a highly effective therapy for hypothyroidism; therefore, physicians should carefully consider levothyroxine therapy and monitor patients’ condition to avoid negative outcomes. Additional studies are needed to confirm these findings and to evaluate the potential biological mechanisms.