Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer.

Impaired base-excision repair (BER) function can give rise to the accumulation of DNA damage and initiation of cancer. We evaluated whether genetic variation in six BER pathway genes (XRCC1, ADPRT, APEX1, OGG1, LIG3, and MUTYH) is associated with breast cancer risk in two large population-based case-control studies in the United States (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). A detailed evaluation was first done in a subset of 1,898 cases and 1,514 controls with mouthwash DNA samples in the U.S. study. Significant findings were followed up in the remainder of the U.S. study population that provided cytobrush DNA samples and in the Polish study. Using data from U.S. study participants with mouthwash DNA, we found no significant overall association between breast cancer risk and XRCC1 R280H and R194W, ADPRT V726W, APEX1 D148E, OGG1 S326C, LIG3 R780H, or MUTYH 5' untranslated region. These data suggested a decreased risk for XRCC1Q399R homozygous variants compared with homozygous wild-type in premenopausal women, but these findings were not confirmed when data from cytobrush DNA samples were added [combined odds ratio (OR), 0.8; 95% confidence interval (95% CI), 0.6-1.1] or in the Polish study (OR, 1.0; 95% CI, 0.7-1.5). Meta-analyses based on our data and published data from studies of two single nucleotide polymorphisms in XRCC1 showed no evidence of an overall association between breast cancer risk and homozygous variants versus wild-type for Q399R (OR, 1.1; 95% CI, 1.0-1.2) or R194W (OR, 1.0; 95% CI, 0.7-1.8), although there was a suggestion for an association in Asian populations for Q399R (OR, 1.6; 95% CI, 1.1-2.4; P = 0.02). In conclusion, our results do not support that the polymorphisms evaluated in six BER pathway genes play a major role in breast carcinogenesis, particularly in Caucasian populations.     

Occupational Exposure to Vinyl Chloride, Acrylonitrile and Styrene and Lung Cancer Risk (Europe)

Several industry-based cohort studies have addressed the risk of lung cancer following exposure to vinyl chloride, acrylonitrile and styrene, with inconsistent results and usually without smoking adjustment. These exposures are addressed here in a large case-control study with full adjustment for smoking. Almost 6000 subjects were included in a case-control study conducted in seven European countries. For each job they held, local experts assessed the exposure to a number of occupational agents, including vinyl chloride, acrylonitrile and styrene, on the basis of detailed occupational questionnaires. Information on tobacco consumption and other risk factors was also collected. The odds ratio (OR) for ever exposure to vinyl chloride was 1.05 (95% confidence interval, CI: 0.68-1.62) and a modest, non-significant increase in the risk of lung cancer was found in the highest exposed subgroup. The OR for ever exposure to acrylonitrile was 2.20 (95% CI: 1.11-4.36) with a positive dose-response relationship between estimated cumulative exposure and lung cancer risk. No association between exposure to styrene and lung cancer risk was found. In conclusion, we cannot exclude a weak association between occupational exposure to vinyl chloride and lung cancer risk. Exposure to acrylonitrile was associated in our study with risk of lung cancer. Exposure to styrene does not seem to increase lung cancer risk.     

Type of Alcoholic Beverage and Risk of Head and Neck Cancer--A Pooled Analysis Within the INHANCE Consortium

The authors pooled data from 15 case-control studies of headand neck cancer (9,107 cases, 14,219 controls) to investigatethe independent associations with consumption of beer, wine,and liquor. In particular, they calculated associations withdifferent measures of beverage consumption separately for subjectswho drank beer only (858 cases, 986 controls), for liquor-onlydrinkers (499 cases, 527 controls), and for wine-only drinkers(1,021 cases, 2,460 controls), with alcohol never drinkers (1,124cases, 3,487 controls) used as a common reference group. Theauthors observed similar associations with ethanol-standardizedconsumption frequency for beer-only drinkers (odds ratios (ORs)= 1.6, 1.9, 2.2, and 5.4 for 5, 6–15, 16–30, and>30 drinks per week, respectively; P_trend < 0.0001) andliquor-only drinkers (ORs = 1.6, 1.5, 2.3, and 3.6; P < 0.0001).Among wine-only drinkers, the odds ratios for moderate levelsof consumption frequency approached the null, whereas thosefor higher consumption levels were comparable to those of drinkersof other beverage types (ORs = 1.1, 1.2, 1.9, and 6.3; P <0.0001). Study findings suggest that the relative risks of headand neck cancer for beer and liquor are comparable. The authorsobserved weaker associations with moderate wine consumption,although they cannot rule out confounding from diet and otherlifestyle factors as an explanation for this finding. Giventhe presence of heterogeneity in study-specific results, theirfindings should be interpreted with caution. alcohol drinking; alcoholic beverages; beer; case-control studies; head and neck neoplasms; meta-analysis; wine     

Glutathione S-transferase polymorphisms, cruciferous vegetable intake and cancer risk in the Central and Eastern European Kidney Cancer Study

High consumption of cruciferous vegetables has been associated with reduced kidney cancer risk in many studies. Isothiocyanates, thought to be responsible for the chemopreventive properties of this food group, are conjugated to glutathione by glutathione S-transferases (GSTs) before urinary excretion. Modification of this relationship by host genetic factors is unknown. We investigated cruciferous vegetable intake in 1097 cases and 1555 controls enrolled in a multicentric case-control study from the Czech Republic, Poland, Romania and Russia. To assess possible gene-diet interactions, genotyped cases (N = 925) and controls (N = 1247) for selected functional or non-synonymous polymorphisms including the GSTM1 deletion, GSTM3 3 bp deletion (IVS6 + 22-AGG) and V224I G>A substitution, GSTT1 deletion and the GSTP1 I105V A>G substitution. The odds ratio (OR) for low (less than once per month) versus high (at least once per week) intake of cruciferous vegetables was 1.29 [95% confidence interval (CI): 1.02-1.62; P-trend = 0.03]. When low intake of cruciferous vegetables (less than once per month) was stratified by GST genotype, higher kidney cancer risks were observed among individuals with the GSTT1 null (OR = 1.86; 95% CI: 1.07-3.23; P-interaction = 0.05) or with both GSTM1/T1 null genotypes (OR = 2.49; 95% CI: 1.08-5.77; P-interaction = 0.05). These data provide additional evidence for the role of cruciferous vegetables in cancer prevention among individuals with common, functional genetic polymorphisms.     

Occupation and risk of lung cancer in Central and Eastern Europe: the IARC multi-center case–control study

Objective We sought to evaluate the role of occupation and industry in lung carcinogenesis in six countries in Central and Eastern Europe. Methods This multi-center case–control study included 2,056 male and 576 female lung cancer incidence cases diagnosed from 1998 to 2001 and 2,144 male and 727 female controls frequency-matched for sex and age. Unconditional regression models were applied to calculate the odds ratios after controlling for potential confounders including age (5-year groups), study center (15 centers), and tobacco pack-years. Results Elevated odds ratios (ORs) were found for men employed as production workers (OR 1.45, 95% CI 1.22–1.72), bookkeepers and cashiers (1.81, 1.03–3.24), general farmers (1.67, 1.08–2.60), livestock workers (2.54, 1.09–5.88), miners (2.17, 1.47–3.23), toolmakers and metal patternmakers (2.56, 1.34–4.94), glass formers (2.55, 1.18–5.50), dockworkers, and freight handlers (1.49, 1.04–2.12). Industries with elevated risk among men included mining (1.75, 1.20–2.57), manufacture of cement, lime, or plaster (3.62, 1.11–12.00), casting of metals (2.00, 1.17–3.45), manufacture of electric motors (2.18, 1.24–3.86). For women, elevated ORs were found for medical, dental, veterinary doctors (2.54, 1.01–6.31), librarians and curators (7.03, 1.80–27.80), sewers 3.63 (1.12–10.23). Conclusions This study identifies new areas for further, explanatory analyses, especially in production work, and indicates new possible sources of exposure to cancer risk for women.     

Reproductive risk factors for endometrial cancer among Polish women

We conducted a population-based case–control study of reproductive factors in Warsaw and Ló∂ź, Poland, in 551 incident endometrial cancer cases and 1925 controls. The reproductive variable most strongly related to risk was multiparity, with subjects with three or more births having a 70% lower risk than the nulliparous women. The reduced risk was particularly strong below 55 years of age. Subjects with older ages at a first birth were also at reduced risk even after adjustment for number of births. Ages at last birth or intervals since last birth were not strongly related to risk. Spontaneous abortions were unrelated to risk, but induced abortions were associated with slight risk increases (odds ratios=1.28, 95% confidence intervals 0.8–2.1 for 3+ vs no abortions). The absence of effects on risk of later ages at, or short intervals since, a last birth fails to support the view that endometrial cancer is influenced by mechanical clearance of initiated cells. Alternative explanations for reproductive effects should be sought, including alterations in endogenous hormones.     

The association of sequence variants in DNA repair and cell cycle genes with cancers of the upper aerodigestive tract

Cancers of the upper aerodigestive tract (UADT), comprising the oral cavity, pharynx, larynx and oesophagus, account for 5.2% of all cancers cases worldwide. The major risk factors, tobacco and alcohol can directly or indirectly generate DNA damage, which if unrepaired can give rise to mutations, unregulated cell growth and apoptosis induction. To clarify the role of DNA repair and cell cycle control proteins in UADT cancer susceptibility, we studied the risk in relation to 28 SNPs in 18 DNA repair enzymes and 9 SNPs in 7 cell cycle control genes. A case-control study was conducted from 2000 to 2002 in six centers from Romania, Poland, Russia, Slovakia and the Czech Republic. Patients diagnosed with squamous cell carcinoma of the UADT (n=811) and controls with a recent diagnosis of diseases unrelated to tobacco and alcohol (n=1083) were recruited. For UADT cancer risk, associations were observed for the homozygous carriers of the variant alleles of MGMT L84F [odds ratio (OR) 2.35, 95% confidence interval (CI) 1.32-4.20], MGMT 171C > T (OR 2.24, 95% CI 1.20-4.17) and OGG1 S326C (OR 2.07, 95% CI 1.15-3.73) whilst three variants were associated with a protective effect (XPA 23G > A, P for trend 0.022, APEX Q51H, P for trend 0.036, CHEK2 intron 9-200T > C, P for trend 0.009). Several other sequence variants showed associations with specific cancers without an overall association with UADT cancer. While some of these associations are consistent with previous studies, we cannot rule out the possibility of false-positive associations. The positive findings should be explored in another large-scale study on UADT cancers.     

Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes

The role of genes coding for xenobiotic metabolizing enzymes (XMEs) and the risk of lung cancer is unclear. Under the assumption that these genes may be more important among people having a diagnosis of lung cancer at younger ages, we have investigated the role of single-nucleotide polymorphisms (SNPs) within phase I and phase II XME genes, and also genes involved in the metabolism of nucleic acids in a series of young onset patients and matched controls. We genotyped 299 lung cancer cases diagnosed before the age of 50 and 317 controls, from six countries of Central and Eastern Europe, by use of an oligonucleotide microarray and arrayed primer extension technique for 45 SNPs in 15 phase I XME genes, 46 SNPs in 17 phase II genes and 9 SNPs in 4 genes related to metabolism of nucleic acids. Heterozygote carriers of SNPs in CYP1A2 1545T>C, -164C>A and -740T>G; CYP2A6 -47A>C; MDR1 3435T>C; NAT1 1088T>A and 1095A>C; GSTA2 S112T; GSTM3 V224I and MTHFR A222V had altered risk of developing lung cancer. Phenotypes reconstructed after haplotype analyses showed that the carriers of the combined NAT1 fast+ NAT2 fast phenotypes were at lower risk when compared with those with the combined NAT1 slow + NAT2 slow acetylator phenotypes. Finally, extensive EPHX1 metabolizers showed an increased risk as compared with the poor metabolizers.     

In-Home Coal and Wood Use and Lung Cancer Risk: A Pooled Analysis of the International Lung Cancer Consortium

Background

Domestic fuel combustion from cooking and heating is an important public health issue because roughly 3 billion people are exposed worldwide. Recently, the International Agency for Research on Cancer classified indoor emissions from household coal combustion as a human carcinogen (group 1) and from biomass fuel (primarily wood) as a probable human carcinogen (group 2A).

Objectives

We pooled seven studies from the International Lung Cancer Consortium (5,105 cases and 6,535 controls) to provide further epidemiological evaluation of the association between in-home solid-fuel use, particularly wood, and lung cancer risk.

Methods

Using questionnaire data, we classified subjects as predominant solid-fuel users (e.g., coal, wood) or nonsolid-fuel users (e.g., oil, gas, electricity). Unconditional logistic regression was used to estimate the odds ratios (ORs) and to compute 95% confidence intervals (CIs), adjusting for age, sex, education, smoking status, race/ethnicity, and study center.

Results

Compared with nonsolid-fuel users, predominant coal users (OR = 1.64; 95% CI, 1.49–1.81), particularly coal users in Asia (OR = 4.93; 95% CI, 3.73–6.52), and predominant wood users in North American and European countries (OR = 1.21; 95% CI, 1.06–1.38) experienced higher risk of lung cancer. The results were similar in never-smoking women and other subgroups.

Conclusions

Our results are consistent with previous observations pertaining to in-home coal use and lung cancer risk, support the hypothesis of a carcinogenic potential of in-home wood use, and point to the need for more detailed study of factors affecting these associations.     

Welding and lung cancer in Central and Eastern Europe and the United Kingdom

Occupation as a welder has been associated with a 25%-40% increase in lung cancer risk. This study aims to elucidate to what extent confounding by smoking and asbestos drives this association and to evaluate the role of welding-related exposures such as chromium. The study included 2,197 male incident lung cancer cases and 2,295 controls from Romania, Hungary, Poland, Russia, Slovakia, the Czech Republic, and the United Kingdom from 1998 to 2001. Information on risk factors was collected through face-to-face interviews. Experts assessed exposure to 70 agents, and risk estimates were adjusted for smoking and occupational exposures. Occupation as a welder/flame cutter (prevalence controls: 3.7%) was associated with an odds ratio of 1.36 (95% confidence interval (CI): 1.00, 1.86) after adjustment for smoking and occupational exposures including asbestos. An odds ratio of 1.18 (95% CI: 1.01, 1.38) was found for welding fumes (prevalence controls: 22.8%), increasing to 1.38 for more than 25 exposure years (95% CI: 1.09, 1.75). A duration-response association was also observed for mild steel welding without chromium exposure. In this population, occupational exposure to welding fumes accounted for approximately 4% of lung cancer cases, to which both stainless and mild steel welding contributed equally. Given that welding remains a common task for many workers, exposure to welding fumes represents an important risk factor for lung cancer.