Jolanta Lissowska

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10−10 and 10−9, respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.

Total Exposure and Exposure Rate Effects for Alcohol and Smoking and Risk of Head and Neck Cancer: A Pooled Analysis of Case-Control Studies

Although cigarette smoking and alcohol consumption increase risk for head and neck cancers, there have been few attempts to model risks quantitatively and to formally evaluate cancer site-specific risks. The authors pooled data from 15 case-control studies and modeled the excess odds ratio (EOR) to assess risk by total exposure (pack-years and drink-years) and its modification by exposure rate (cigarettes/day and drinks/day). The smoking analysis included 1,761 laryngeal, 2,453 pharyngeal, and 1,990 oral cavity cancers, and the alcohol analysis included 2,551 laryngeal, 3,693 pharyngeal, and 3,116 oval cavity cancers, with over 8,000 controls. Above 15 cigarettes/day, the EOR/pack-year decreased with increasing cigarettes/day, suggesting that greater cigarettes/day for a shorter duration was less deleterious than fewer cigarettes/day for a longer duration. Estimates of EOR/pack-year were homogeneous across sites, while the effects of cigarettes/day varied, indicating that the greater laryngeal cancer risk derived from differential cigarettes/day effects and not pack-years. EOR/drink-year estimates increased through 10 drinks/day, suggesting that greater drinks/day for a shorter duration was more deleterious than fewer drinks/day for a longer duration. Above 10 drinks/day, data were limited. EOR/drink-year estimates varied by site, while drinks/day effects were homogeneous, indicating that the greater pharyngeal/oral cavity cancer risk with alcohol consumption derived from the differential effects of drink-years and not drinks/day.

Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses.

Epidemiological evidence suggests that intake of folate and other B‐vitamins and genetic variants in the one‐carbon metabolism pathway could influence the risk of breast cancer. Previous studies have focused on 2 polymorphisms in the methylenetetrahydrofolate gene (MTHFR A222V and E429A); however, findings are inconclusive. In a large population‐based case–control study in Poland (2,386 cases, 2,502 controls), we investigated the association between breast cancer risk and 13 polymorphisms in 6 one‐carbon metabolism genes (MTHFR, MTR, MTRR, CBS, SHMT1 and SLC19A1). Data suggested an association between a nonsynonymous change in the gene coding for methionine synthase (MTR D919G) and reduced breast cancer risk: OR (95% CI) = 0.84 (0.73–0.96) and 0.85 (0.62–1.15) for heterozygous and homozygote variant genotypes, respectively, compared with common homozygotes; p‐trend = 0.01, false discovery rate = 0.14. We found no significant associations between other variants and breast cancer risk, including MTHFR A222V or E429A. Meta‐analyses including published studies of MTHFR A222V (8,330 cases and 10,825 controls) and E429A (6,521 cases and 8,515 controls) supported the lack of an overall association; however, studies suggested an increase in risk among premenopausal women. In conclusion, this report does not support a substantial overall association between the evaluated polymorphisms in the one‐carbon metabolism pathway and breast cancer risk.

Glutathione S-transferase genotypes and stomach cancer in a population-based case-control study in Warsaw, Poland

Glutathione S-transferases are important in the detoxification of a wide range of human carcinogens. Previous studies have shown inconsistent associations between the GSTT1 and GSTM1 null genotypes and stomach cancer risk. We investigated the relationship between these and related genotypes and stomach cancer risk in a population-based case-control study in Warsaw, Poland, where stomach cancer incidence and mortality rates are among the highest in Europe. DNA from blood samples was available for 304 stomach cancer patients and 427 control subjects. We observed a 1.48-fold increased risk for stomach cancer (95% confidence interval 0.97-2.25) in patients with the GSTT1 null genotype but no evidence of increased risk associated with the GSTM1, GSTM3 or GSTP1 genotypes. Furthermore, the stomach cancer risk associated with the GSTT1 null genotype varied by age at diagnosis, with odds ratios of 3.85, 1.91, 1.78 and 0.59 for those diagnosed at ages less than 50, 50-59, 60-69 and 70 years or older, respectively (P trend = 0.01). This was due to a shift in the GSTT1 genotype distribution across age groups among stomach cancer patients only. These results suggest that the GSTT1 null genotype may be associated with increased risk of stomach cancer.

DNA Hypermethylation of ESR1 and PGR in Breast Cancer: Pathologic and Epidemiologic Associations

Improved understanding of the etiology of estrogen receptor-α (ERα)–negative and progesterone receptor (PR)–negative breast cancers may permit improved risk prediction. In vitro studies implicate DNA hypermethylation of the ERα and PR promoters in the pathogenesis of ERα-negative and PR-negative tumors, but results are not definitive. We evaluated 200 invasive breast cancers selected from a population-based case-control study. DNA extracted from fixed tumor tissue cores was tested using MethyLight to assess DNA methylation at four CpG islands: ESR1 promoters A and B; PGR promoters A and B; and a CpG shore, ESR1 promoter C. DNA methylation results were compared with levels of ERα and PR, tumor characteristics, and breast cancer risk factors. We observed mild to moderate DNA methylation levels in most tumors for ESR1 promoters A and B and PGR promoter B, and a few tumors showed mild methylation in PGR promoter A. In contrast, ESR1 promoter C showed a wide range of methylation and was weakly correlated with lower expression levels of ERα (β = −0.26; P < 0.0001) and PR (β = −0.25; P < 0.0001). The percentage of tumors with methylated PGR promoters A and B was significantly higher for tumors with low ERα (A, Fishers test P = 0.0001; B, P = 0.033) and PR levels (A, P = 0.0006; B, P = 0.001). Our data suggest that the relationships between DNA methylation of ESR1 and PGR promoters and protein expression are weak and unlikely to represent a predominant mechanism of receptor silencing. In contrast to CpG islands, ESR1 promoter C showed a wider range of methylation levels and inverse associations with ERα and PR expression. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3036–43)

Tobacco smoking, NAT2 acetylation genotype and breast cancer risk

The role of active and passive cigarette smoking in breast cancer etiology remains controversial. Using data from a large population‐based case‐control study in Poland (2386 cases, 2502 controls) conducted during 2000–2003, we examined the associations between active and passive smoking overall and for different age categories. We also evaluated differences in risk by estrogen receptor (ER) and progesterone receptor (PR) status in tumors, and the potential modification of the smoking association by N‐acetyl transferase 2 (NAT2) genotype. Women ever exposed to passive smoking at home or at work had a risk of breast cancer similar to those never exposed to active or passive smoking (OR (95%CI) = 1.11 (0.85–1.46), and no trends were observed with increasing hours/day‐years of passive smoking exposure. Active smoking was associated with a significant increase in risk only among women younger than 45 years of age (OR (95%CI) = 1.95 (1.38–2.76); 1.15 (0.93–1.40); 0.91 (0.77–1.09) for <45, 45–55 and >55 years of age, respectively; p‐heterogeneity <0.001 for <45 vs. >55 years) and prevailed for both ER+ and ER− tumors. The smoking association among women <45 years was stronger for current than former smokers, and a significant trend was observed with duration of smoking (p = 0.04). NAT2 slow vs. rapid/intermediate acetylation genotype was not related to breast cancer risk (0.99 (0.87–1.13)), and did not significantly modify the smoking relationships. In conclusion, our data indicate that passive smoking is not associated with breast cancer risk; however, active smoking might be associated with an increased risk for early onset breast cancers.

Genetic Polymorphisms in Folate Metabolism and the Risk of Stomach Cancer

Folate deficiency has been implicated in the etiology of stomach cancer through abnormal DNA methylation and disrupted DNA synthesis and repair. Enzyme-coding genes involved in folate metabolism are often polymorphic. In a population-based study of 305 cases and 427 controls in Warsaw, Poland, we evaluated the risk of stomach cancer in relation to polymorphisms in folate-metabolizing genes, including MTHFR (Ex5+79C>T and Ex8−62A>C), MTR (Ex26−20A>G), and MTRR (Ex2−64A>G, Ex5+123C>T, Ex15+572C>T, Ex15−405A>T, Ex9−85C>T, Ex15−526G>A, and Ex14+14C>T). Polymorphisms in the MTHFR gene were not associated with stomach cancer risk. No notable effect was found for polymorphisms in MTR or MTRR either, although MTR Ex26−20 A>G and MTRR Ex5+123C>T polymorphisms were associated with a borderline increased risk of stomach cancer (MTR Ex26−20A>G, AG/GG versus AA: odds ratio, 1.35; 95% confidence interval, 0.96-1.90; MTRR Ex5+123C>T, CT/TT versus CC: odds ratio, 1.30; 95% confidence interval, 0.93-1.82). We did not find significant interactions between polymorphisms in MTHFR, MTR, and MTRR genes and dietary folate and alcohol consumption. Our study did not identify strong genetic determinants in the folate metabolism pathway for stomach cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(1):115–21)

Lung Cancer and Occupation in Nonsmokers: A Multicenter Case-Control Study in Europe.

Background: Tobacco smoking is the main cause for lung cancer worldwide, making it difficult to examine the carcinogenic role of other risk factors because of possible confounding by smoking. Therefore, the present study aimed to investigate the association between lung cancer and occupation independent of smoking. Methods: A case–control study of lung cancer was carried out between March 1998 and January 2002 in 16 centers from 7 European countries, including 223 never-smoking cases and 1039 controls. Information on lifestyle and occupation was obtained through detailed questionnaires. Job and industries were classified as entailing exposure to known or suspected carcinogens; in addition, expert assessment provided exposure estimates to specific agents. Results: The odds ratio of lung cancer among women employed for more than 12 years in suspected high-risk occupations was 1.75 (95% confidence interval = 0.63–4.85). A comparable increase in risk was not detected for employment in established high-risk occupations or among men. Increased risk of lung cancer was suggested among individuals exposed to nonferrous metal dust and fumes, crystalline silica, and organic solvents. Conclusion: Occupations were found to play a limited role in lung cancer risk among never-smokers. Jobs entailing exposure to suspected lung carcinogens should receive priority in future studies among women. Nonferrous metal dust and fumes and silica may exert a carcinogenic effect independently from smoking.

Genetic variation in SIPA1 in relation to breast cancer risk and survival after breast cancer diagnosis.

Genetic variation in SIPA1, signal‐induced proliferation‐associated gene 1, has been proposed to be associated with aggressive breast tumor characteristics related to metastasis and worse prognosis in humans and rodents. To test this hypothesis, we genotyped 3 single nucleotide polymorphisms (SNP) located at −3092 (AT, rs3741378), and exon 14 + 14 (C>T, rs746429), and examined them in relation to breast cancer risk and overall survival, stratified by tumor characteristics in 2 independent case–control studies conducted in Poland (1,995 cases, 2,296 controls) and in Britain (2,142 cases, 2,257 controls). Vital status (n = 396 deaths) was available for 911 Polish and 1,919 British breast cancer cases with an average follow‐up time of 5.5 years. Overall, we found no significant associations between genetic variants of SIPA1 SNPs and breast cancer risk (per allele odds ratios, 95% confidence intervals (CI): rs931127–0.99, 0.93–1.06; rs3741378–1.03, 0.94–1.13; and, rs74642–0.98, 0.92–1.04). In both studies, SIPA1 polymorphisms were not related to overall mortality (per allele hazard ratios, 95% CI: 1.02, 0.88–1.17; 0.90, 0.72–1.11; 1.04, 0.90–1.21, respectively). Our results do not support a relationship between SIPA1 polymorphisms and breast cancer risk or subsequent survival. Published 2008 Wiley‐Liss, Inc.

Active and passive cigarette smoking and the risk of endometrial cancer in Poland

BACKGROUND Epidemiological studies have consistently reported that active cigarette smoking is inversely associated with endometrial cancer risk. However, dose-response relationships with quantitative measures of active smoking or passive smoking remain less clear. METHODS Data on lifetime active and passive smoking were collected for 551 endometrial cancer cases and 1925 controls in a population-based case-control study conducted during 2001-2003 in Poland (Warsaw and Łódz). RESULTS Compared with never active smokers, active current (Odds Ratio (OR)=0.51, 95% Confidence Interval (CI): 0.39, 0.68) and former smokers (OR=0.60, 95% CI: 0.45, 0.80) were at a statistically significantly decreased risk. We did not observe statistically significant inverse dose-response relationships with increasing exposure with duration and cumulative measures. However, there was some indication that the highest category of number of years (OR=0.35, 95% CI: 0.23-0.55), intensity (OR=0.41, 95% CI: 0.24-0.69), and dose (OR=0.38, 95% CI: 0.24-0.60) of smoking among current smokers had the greatest inverse association compared to never smokers. Our data did not support the presence of an inverse association with passive smoking among never active smokers (OR=0.92; 95% CI: 0.65, 1.29). CONCLUSION Our results support that long-term and heavy smoking among current smokers strongly influence endometrial cancer risk.