Agnieszka Bukowska

Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. Cancer Epidemiol Biomarkers Prev; 21(7); 1156–. ©2012 AACR.

Association of Rotating Night Shift Work with BMI and Abdominal Obesity among Nurses and Midwives.

Background Mounting epidemiological evidence suggests that night shift work may contribute to the etiology of increased body weight. The present study aimed to examine association between rotating night shift work and body mass index (BMI), and abdominal adiposity respectively among nurses and midwives. Methods A cross-sectional study was conducted among 724 female nurses and midwives, aged 40-60 years (354 rotating night shift and 370 daytime workers) in Łódź, Poland, between 2008 and 2011. Information about occupational history and potential confounders was collected during personal interviews. Anthropometric measurements of body weight, height, waist (WC) and hip (HC) circumference were made, and body mass index (BMI), waist to hip ratio (WHR) and waist to height ratio (WHtR) were calculated. GLM regression models and multinomial logit regression models were fitted to explore the association between night shift work and anthropometric parameters, with adjustment for age, body silhouette at age 20, current smoking status, packyears, marital status, and menopausal hormone therapy use. Results Cumulative night shift work showed significant associations with BMI, WC, HC and WHtR, with BMI increasing by 0.477 kg/m2 per 1000 night duties and by 0.432 kg/m2 per 10000 night shift hours, WC increasing respectively by 1.089 cm and 0.99 cm, and HC by 0.72 cm and WHtR by 0.007 cm for both metrics. Both current and cumulative night work was associated with obesity (BMI≥30kg/m2), with OR=3.9 (95%CI:1.5-9.9), in women reporting eight or more night shifts per month. Conclusion The results of the study support the previously reported relations between night shift work and development of obesity.

Night shift work characteristics and 6-sulfatoxymelatonin (MT6s) in rotating night shift nurses and midwives

Objectives Synthesis of melatonin follows a circadian cycle, with high melatonin levels during the night and low levels during the day. Light exposure at night has been hypothesised as one of potential mechanisms of breast carcinogenesis in the night shift workers through inhibition of melatonin synthesis. The aim of the study was to examine a number of determinants for night shift work in relation to 6-sulfatoxymelatonin (MT6s), primary melatonin metabolite. Methods The cross-sectional study included 354 nurses and midwives (aged 40–60 years) currently working on rotating night shifts and 370 working days only. Data from questionnaires and 1-week diaries were used to characterise current job and total occupational history. Associations between rotating night shift work characteristics and MT6s (creatinine adjusted) in spot morning urine were tested in multiple linear regression models. Results No significant differences were found for MT6s concentrations between women currently working on rotating night shifts and those working only day shifts (means 47.2 vs 45.7 ng/mg Cr, respectively). The adjusted means among rotating night shift nurses and midwives varied depending on the department of employment, from 35.1 ng/mg Cr in neonatology to 68.2 ng/mg Cr in the orthopaedics department. Women working eight or more night shifts per month had significantly lower MT6s levels than those having fewer night shifts per month (37.9 vs 47.4 ng/mg Cr, respectively). Total night shift work history was not associated with MT6s. Conclusions The results of this study indicate that working eight or more night shifts per month may disrupt the synthesis of melatonin.

Rotating night shift work and polymorphism of genes important for the regulation of circadian rhythm.

OBJECTIVE People living in industrialized societies have developed specific working schedules during the day and at night, including permanent night shifts and rotating night shifts. The aim of this study was to examine the association between circadian polymorphisms and rotating night shift work. METHODS This cross-sectional study comprised 709 nurses and midwives (348 current rotating and 361 current day workers). Genetic polymorphism of selected clock genes BMAL1 (rs2279287), CLOCK (rs1801260), PER1 (rs2735611), PER2 (rs2304672), PER3 (rs10462020), CRY1 (rs8192440), CRY2 (rs10838527, rs10838527) was determined using real-time polymerase chain reaction (PCR) assays. RESULTS There were no differences in BMAL1, CLOCK, CRY2, PER1, PER2, and PER3 genotypes among nurses and midwives working rotating night and day shifts. The frequency of women with rare CRY1 TT genotype was higher in the group of rotating night shift than day workers (17.0% versus 13.9%, P=0.06). Moreover, CRY1 TT genotype was associated with the total rotating shift-work duration, compared to women rarely working night shifts. CONCLUSIONS These results suggest that CRY1 (rs8192440) polymorphism may influence the adaptation to the rotating night shift work among nurses and midwives.

Lipid peroxidation and glutathione peroxidase activity relationship in breast cancer depends on functional polymorphism of GPX1

BackgroundSince targeting oxidative stress markers has been recently recognized as a novel therapeutic target in cancer, it is interesting to investigate whether genetic susceptibility may modify oxidative stress response in cancer. The aim of this study was to elucidate whether genetic polymorphism in the antioxidant enzymes is associated with lipid peroxidation in breast cancer.MethodsWe conducted a study among Polish women, including 136 breast cancer cases and 183 healthy controls. The analysis included genetic polymorphisms in five redox related genes: GPX1 (rs1050450), GPX4 (rs713041), SOD2 (rs4880), SEPP1 (rs3877899) and SEP15 (rs5859), lipid peroxidation, the activities of antioxidant enzymes determined in blood compartments as well as plasma concentration of selenium – an antioxidant trace element involved in cancer. Genotyping was performed using the Real Time PCR. Lipid peroxidation was expressed as plasma concentration of thiobarbituric acid reactive substances (TBARS) and measured with the spectrofluorometric method. Glutathione peroxidase activity was spectrophotometrically determined in erythrocytes (GPx1) and plasma (GPx3) by the use of Paglia and Valentine method. Spectrophotometric methods were employed to measure activity of cytosolic superoxide dismutase (SOD1) in erythrocytes (Beauchamp and Fridovich method) and ceruloplasmin (Cp) in plasma (Sunderman and Nomoto method). Plasma selenium concentration was determined using graphite furnace atomic absorption spectrophotometry.ResultsBreast cancer risk was significantly associated with GPX1 rs1050450 (Pro198Leu) polymorphism, showing a protective effect of variant (Leu) allele. As compared to the control subjects, lipid peroxidation and GPx1 activity were significantly higher in the breast cancer cases, whereas ceruloplasmin activity was decreased. After genotype stratification, both GPx1 activity and TBARS concentration were the highest in GPX1 Pro/Pro homozygotes affected by breast cancer. At the same time, there was a significant correlation between the level of lipid peroxidation and GPx1 activity among the cancer subjects possessing GPX1 Pro/Pro genotype (r = 0.3043; p = 0.0089), whereas such a correlation was completely absent in the cases carrying at least one GPX1 Leu allele as well as in the controls (regardless of GPX1 genotype).ConclusionsGPX1 polymorphism may be an important factor modifying oxidative stress response in breast cancer subjects. Further studies are needed to elucidate its potential clinical significance.

Night shift work and modifiable lifestyle factors

ObjectivesNight shift work has been linked to some chronic diseases. Modification of lifestyle by night work may partially contribute to the development of these diseases, nevertheless, so far epidemiological evidence is limited. The aim of the study was to explore association between night shift work and lifestyle factors using data from a cross-sectional study among blue-collar workers employed in industrial plants in Łódź, Poland.Material and MethodsThe anonymous questionnaire was self-administered among 605 employees (236 women and 369 men, aged 35 or more) — 434 individuals currently working night shifts. Distribution of the selected lifestyle related factors such as smoking, alcohol drinking, physical activity, body mass index (BMI), number of main meals and the hour of the last meal was compared between current, former, and never night shift workers. Adjusted ORs or predicted means were calculated, as a measure of the associations between night shift work and lifestyle factors, with age, marital status and education included in the models as covariates.ResultsRecreational inactivity (defined here as less than one hour per week of recreational physical activity) was associated with current night shift work when compared to never night shift workers (OR = 2.43, 95% CI: 1.13–5.22) among men. Alcohol abstinence and later time of the last meal was associated with night shift work among women. Statistically significant positive relationship between night shift work duration and BMI was observed among men (p = 0.029).ConclusionsThis study confirms previous studies reporting lower exercising among night shift workers and tendency to increase body weight. This finding provides important public health implication for the prevention of chronic diseases among night shift workers. Initiatives promoting physical activity addressed in particular to the night shift workers are recommended.

Circadian gene expression in peripheral blood leukocytes of rotating night shift nurses

OBJECTIVE It has been hypothesized that the underlying mechanism of elevated breast cancer risk among long-term, night-working women involves circadian genes expression alteration caused by exposure to light at night and/or irregular work hours. The aim of the present study was to determine the effect of rotating night shift work on expression of selected core circadian genes. METHODS The cross-sectional study was conducted on 184 matched nurses and midwives, who currently work either day or rotating night shifts, to determine the effect of irregular work at night on circadian gene expression in peripheral blood leukocytes. Transcript levels of BMAL1, CLOCK, CRY1, CRY2, PER1, PER2, and PER3 were determined by means of quantitative real-time polymerase chain reaction (PCR). RESULTS After adjusting for hour of blood collection, there were no statistically significant changes of investigated circadian genes among nurses and midwives currently working rotating night shifts compared to nurses working day shifts. The highest expression of PER1 messenger ribonucleic acid (mRNA) was observed for women currently working shifts who had worked >15 years in rotating night shift work. PER1 gene expression was associated with the lifetime duration of rotating night shift work among women currently working night shifts (P=0.04). PER1 and PER3 transcript levels in blood leukocytes were significantly down-regulated in the later versus early hours of the morning between 06.00-10.00 hours (β-coefficient -0.226, P=0.001 and β-coefficient -0.181, P<0.0001, respectively). CONCLUSIONS These results suggest that current rotating night shift work does not affect circadian gene expression in human circulating leukocytes. In analysis of the peripheral clock in human studies, the hour of blood collection should be precisely specified.

Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

Background Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. Methods and findings We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. Conclusions Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

Rotating night shift work and physical activity of nurses and midwives in the cross-sectional study in Łódź, Poland

Shift work have been thought to restrict participation in leisure time activities, but the knowledge about physical activity in rotating night shift nurses has been limited so far. We investigated the associations between the rotating night shift work and physical activity using data from a cross-sectional study among nurses and midwives. This study included 354 nurses and midwives (aged 40–60) currently working rotating night shifts and 371 ones working days only. The information on the work characteristics and potential covariates was collected via a personal interview. Weight and height were measured and BMI was calculated. Physical activity was assessed according to the international questionnaire on physical activity – IPAQ, and four domains: leisure time, occupational, transport related and household were analyzed. Women who reported none leisure time activity were defined as recreationally “inactive”. The associations were examined with multiple linear or logistic regression models adjusted for age, season of the year, number of full term births, marital status and BMI. Total and occupational physical activity was significantly higher among nurses working rotating night shifts. However, leisure time activity was significantly affected among rotating night shift nurses and midwives, compared to women working during the days only, with increased odds ratio for recreational “inactivity” (OR = 1.57, 95% CI: 1.11–2.20). Rotating night shift work among nurses and midwives is associated with higher occupational physical activity but lower leisure time activity. Initiatives supporting exercising among night shift workers are recommended.

Rotating Night Shift Work and Mammographic Density

Background: An increased risk of breast cancer has been observed in night shift workers. Exposure to artificial light at night and disruption of the endogenous circadian rhythm with suppression of the melatonin synthesis have been suggested mechanisms. We investigated the hypothesis that rotating night shift work is associated with mammographic density. Methods: We conducted a cross-sectional study on the association between rotating night shift work characteristics, 6-sulfatoxymelatonin (MT6s) creatinine adjusted in a spot morning urine sample, and a computer-assisted measure of mammographic density in 640 nurses and midwives ages 40 to 60 years. The associations were evaluated using regression models adjusted for age, body mass index, menopausal status, age at menopause, age at menarche, smoking, and the calendar season of the year when mammography was conducted. Results: The adjusted means of percentage of mammographic density and absolute density were slightly higher among women working rotating night shifts but not statistically significant [percentage of mammographic density = 23.6%, 95% confidence interval (CI), 21.9%–25.4% vs. 22.5%, 95% CI, 20.8%–24.3%; absolute density = 23.9 cm2, 95% CI, 21.4–26.4 cm2 vs. 21.8 cm2, 95% CI, 19.4–24.3 cm2 in rotating night shift and day shift nurses, respectively). There were no significant associations between the current or cumulative rotating night shift work exposure metrics and mammographic density. No association was observed between morning MT6s and mammographic density. Conclusions: The hypothesis on the link between rotating night shift work, melatonin synthesis disruption, and mammographic density is not supported by the results of the present study. Impact: It is unlikely that the development of breast cancer in nurses working rotating night shifts is mediated by an increase in mammographic density. Cancer Epidemiol Biomarkers Prev; 21(7); 1028–37. ©2012 AACR.