Sexually and non-sexually transmitted infections and the risk of prostate cancer: Results from the EPICAP study.

INTRODUCTION: Prostate cancer (PCa) is by far the most common type of cancer among men in western countries. However, relatively little is known about its etiology despite the high morbidity and mortality. It has been suggested that chronic inflammation may be involved in prostate carcinogenesis. We investigated the role of sexually and non-sexually transmitted infections in prostate cancer risk with a specific interest in the aggressive types. METHODS: We used data from epidemiological study of prostate cancer (EPICAP), a population-based case-control study. A total of 819 incident cases and 879 controls were interviewed face-to-face using a standardized questionnaire gathering information on known or suspected risk factors of prostate cancer and personal history of specific sexually and non-sexually transmitted infections: gonorrhea, syphilis, trichomonas, herpes, mononucleosis, Epstein-Barr virus, varicella-zoster, and dengue. Odds ratios (OR) and their 95% confidence interval were estimated using multivariate unconditional logistic regression. RESULTS: There was no significant association between gonorrhea (OR: 0.90, 95% CI: 0.61-1.33), trichomonas (OR: 0.74, 95% CI: 0.27-2.07), genital herpes (OR: 0.69, 95% CI: 0.38-1.27), and the risk of prostate cancer. No association emerged for overall sexually transmitted bacterial and viral infections (OR 1.05, 95% CI: 0.86-1.29) and overall non-sexually transmitted viral infections (OR 1.11, 95% CI: 0.90-1.35) and the risk of prostate cancer. CONCLUSION: Our results showed that sexually or non-sexually transmitted infections, either bacterial or viral, were not associated to prostate cancer. Therefore, further investigation is needed to help advance our understanding of the role of chronic inflammation in the etiology of prostate cancer, with a particular focus on its most aggressive types.

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry.

BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. RESULTS: Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.

Sleep Traits, Night Shift Work and Lung Cancer Risk among Women: Results from a Population-Based Case-Control Study in France (The WELCA Study).

Circadian rhythm disruption due to night shift work and/or sleep disorders is associated with negative health outcomes including cancer. There is only scant evidence of an association with lung cancer, unlike breast and prostate cancer. We explore the role of sleep disorders and night shift work in lung cancer risk among women in a population-based case-control study, including 716 lung cancer cases and 758 controls. Multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with sleep duration per day (<7 h, 7−7.9 h, ≥8 h), a summary index of sleep disorders, chronotype, and night shift work exposure metrics. When compared to women with an average sleep duration of 7−7.9 h per day, the OR was 1.39 (95% CI 1.04−1.86) in long sleepers (≥8 h) and 1.16 (95% CI 0.86−1.56) in short sleepers (<7 h). Overall, lung cancer was not associated with the sleep disorder index, nor with night shift work, regardless of the duration of night work or the frequency of night shifts. However, elevated OR associated with the sleep disorder index were found in the subgroup of current smokers. The U-shaped association of lung cancer with sleep duration was more particularly pronounced among women who worked at night ≥5 years. Our findings suggested that sleep patterns are associated with lung cancer risk in women with a potential modifying effect by night shift work duration or tobacco smoking.

Diabetes, metabolic syndrome and prostate cancer risk: Results from the EPICAP case-control study.

BACKGROUND: Diabetes may be associated with decreased prostate cancer (PCa) risk. However, previous studies have not always accounted for time since diabetes diagnosis or antidiabetic drug use. Futhermore, the role of metabolic syndrome (MetS) in PCa risk is still debated. We investigated the role of diabetes and MetS in PCa risk based on data from the Epidemiological study of PCa (EPICAP). METHODS: EPICAP is a population-based case-control study that included 819 incident PCa cases in 2012-2013 and 879 controls frequency matched by age. MetS was characterized according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III). Logistic regression models adjusted for age, family history of PCa and ethnicity, were used to assess odds ratios (ORs) and their 95%conficence intervals (CIs) for the associations between diabetes, MetS and PCa risk. RESULTS: Whereas we did not observed an association between diabetes and PCa, a decreased risk of PCa has been highlighted with an increasing treated diabetes duration (p-trend=0.008). No association has been observed between MetS, the number of MetS criteria and the risk of PCa. However, we suggested that NSAIDs use could modify the association between MetS and PCa risk. CONCLUSION: Our results suggest an inverse association between the duration of diabetes and PCa risk. The role of metabolic factors, such as MetS and its components, in PCa risk remains unclear and requires further investigations.

Sleep Patterns and Risk of Prostate Cancer: A Population-Based Case Control Study in France (EPICAP).

BACKGROUND: Sleep disturbances have been singled out for their implication in the risk of several cancer sites. However, results for prostate cancer are still inconsistent. METHODS: We used data from the EPICAP study, a French population-based case-control study including 819 incident prostate cancer cases and 879 controls frequency matched by age. Detailed information on sleep duration on work/free days, and sleep medication over lifetime was collected. RESULTS: Sleep duration and sleep deprivation were not associated with prostate cancer, whatever the aggressiveness of prostate cancer. However, sleep deprivation was associated with an increased prostate cancer risk among men with an evening chronotype [OR, 1.96; 95% confidence interval (CI), 1.04-3.70]. We also observed an increased risk of prostate cancer with higher duration of sleep medication use (Ptrend = 0.008). This association with long duration of sleep medication use (≥10 years) was more pronounced among men who worked at night 15 years or more (OR, 3.84; 95% CI, 1.30-11.4) and among nonusers of NSAID (OR, 2.08; 95% CI, 1.15-3.75). CONCLUSIONS: Our results suggested that chronotype, night work, or NSAID use could modify the association between sleep disorders and prostate cancer occurrence needing further investigations to go further. IMPACT: EPICAP is the first study, which investigates several sleep indicators taking into account potential effect modifiers. If our findings were confirmed, we could identify subgroups of men at higher risk of prostate cancer that may be accessible to preventive measures.

Immune disruptions and night shift work in hospital healthcare professionals: The intricate effects of social jet-lag and sleep debt.

Objectives: We aimed to examine the effects of circadian and sleep rhythm disruptions on immune biomarkers among hospital healthcare professionals working night shifts and rotating day shifts. Methods: Hospital nurses working either as permanent night shifters (n=95) or as day shifters rotating between morning and afternoon shifts (n=96) kept a daily diary on their sleep and work schedules over a full working week. Blood samples were collected at the beginning and end of the last shift during the week, and participants were categorized into three groups based on work shift: morning shift (39 day shifters sampled at 7:00 and 14:00), afternoon shift (57 day shifters sampled at 14:00 and 21:00), and night shift (95 night shifters sampled at 21:00 and 7:00). Circulating blood counts in immune cells, interleukin-6 and C-reactive protein concentrations as well as total sleep time per 24 hours during work days (TST24w) and free days (TST24f), sleep debt (TST24f - TST24w) and social jet-lag (a behavioral proxy of circadian misalignment) were assessed. Results: Compared with day shifters, night shifters had shorter sleep duration (TST24w=5.4 ± 1.4h), greater sleep debt (3.2 ± 1.4 h) and social jet-lag (6.7 ± 2.4 h). Variations of immune biomarkers concentrations were consistent with the expected diurnal variations among day shifters (i.e., low level in the morning, increase during the day, peak value in the evening). By contrast, in night shifters, blood concentrations of total lymphocytes, T-helper cells, cytotoxic T-cells, memory B-cells and interleukin-6 were lower at 21:00, increased during the night, and reached higher values at 7:00. Multivariate analyses ruled out significant impact of TST24w, sleep debt, and social jet-lag on immune biomarkers concentrations among day shifters. In contrast, among night shifters, multivariate analyses indicated a combined effect of total sleep time (TST24w), sleep debt and social jet-lag for total lymphocytes and T-helper cells but only a social jet-lag effect for interleukin-6 and a single total sleep time effect for neutrophil and B-Cells. Conclusions: Altogether, our results point to intricate response patterns of immune rhythms to circadian misalignment and sleep debt in night shifters. Specifically, these altered pattern expressions of immune cells may increase vulnerability to infections and reduce vaccination efficiency in night workers.

A 34-year overview of night work by occupation and industry in France based on census data and a sex-specific job-exposure matrix.

BACKGROUND: Night work has been increasing in the last decades due to new working arrangements for good and services production. Numerous studies have shown that night shift work causes disruptions in circadian rhythms that may affect health. In 2019, night shift work was classified as probably carcinogenic to humans by the International Agency for Research on Cancer, and may contribute to other health disorders. In this context, we assessed the number and proportion of workers exposed to night work today and investigated time trends by occupation and industry in France since 1982 in terms of prevention. METHODS: Using the data on work time schedules collected in the French Labour Force Surveys, sex- and period-specific job-exposure matrices (JEMs) to night work (working between midnight and 5 AM) were developed. After linkage of the JEMs with data of the national censuses of 1982, 1990, 1999, 2007 and 2015, the numbers and proportions of workers usually or occasionally exposed to night work were estimated. RESULTS: The number of night workers (usual and occasional) increased from 3.67 million in 1982 to 4.37 million in 2015 (15.8% vs 16.4%). Night work was more common in men than in women (e.g. 22.4% vs 10.0% in 2015), and usual night work largely increased after 2000 (4.4% in 1999, 7.2% in 2007). In 2015, 1.29 million men worked usually at night, including 882,000 workers in the service sector (63%) and 360,000 in the manufacturing and extracting industries (28%). For the same period, 581,000 women were usual night workers, most of them being employed in the service sector (90%). Among women, a 97% increase of usual night work was observed between 1982 and 2015. CONCLUSIONS: This study shows that night work involves a growing number of workers in France, particularly in women in the service sector. These results raise concern about the public health impact of night work and particularly about the numbers of outcomes attributable to this exposure such as breast or prostate cancers.

Digital circadian and sleep health in individual hospital shift workers: A cross sectional telemonitoring study.

BACKGROUND: Telemonitoring of circadian and sleep cycles could identify shift workers at increased risk of poor health, including cancer and cardiovascular diseases, thus supporting personalized prevention. METHODS: The Circadiem cross-sectional study aimed at determining early warning signals of risk of health alteration in hospital nightshifters (NS) versus dayshifters (DS, alternating morning and afternoon shifts). Circadian rhythmicity in activity, sleep, and temperature was telemonitored on work and free days for one week. Participants wore a bluetooth low energy thoracic accelerometry and temperature sensor that was wirelessly connected to a GPRS gateway and a health data hub server. Hidden Markov modelling of activity quantified Rhythm Index, rest quality (probability, p1-1, of remaining at rest), and rest duration. Spectral analyses determined periods in body surface temperature and accelerometry. Parameters were compared and predictors of circadian and sleep disruption were identified by multivariate analyses using information criteria-based model selection. Clusters of individual shift work response profiles were recognized. FINDINGS: Of 140 per-protocol participants (133 females), there were 63 NS and 77 DS. Both groups had similar median rest amount, yet NS had significantly worse median rest-activity Rhythm Index (0·38 [IQR, 0·29-0·47] vs. 0·69 [0·60-0·77], p<0·0001) and rest quality p1-1 (0·94 [0·94-0·95] vs 0·96 [0·94-0·97], p<0·0001) over the whole study week. Only 48% of the NS displayed a circadian period in temperature, as compared to 70% of the DS (p=0·026). Poor p1-1 was associated with nightshift work on both work (p<0·0001) and free days (p=0·0098). The number of years of past night work exposure predicted poor rest-activity Rhythm Index jointly with shift type, age and chronotype on workdays (p= 0·0074), and singly on free days (p=0·0005). INTERPRETATION: A dedicated analysis toolbox of streamed data from a wearable device identified circadian and sleep rhythm markers, that constitute surrogate candidate endpoints of poor health risk in shift-workers. FUNDING: French Agency for Food, Environmental and Occupational Health & Safety (EST-2014/1/064), University of Warwick, Medical Research Council (United Kingdom, MR/M013170), Cancer Research UK(C53561/A19933).

Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women.

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.

Occupation and prostate Cancer risk: results from the epidemiological study of prostate cancer (EPICAP).

BACKGROUND: Although prostate cancer (PCa) is the most frequent male cancer in industrialized countries, little is known about its aetiology. The literature has suggested an influence of the environment, including occupational exposures, but results are inconsistent. In this context, we investigated PCa risk associated to employment among several occupations using data from EPICAP study. METHODS: EPICAP is a French population-based case-control study including 819 PCa incident cases and 879 controls frequency-matched on age. In-person interviews gathered data on potential risk factors and lifetime occupational histories for each job held at least 6 months. Then, occupations were coded using ISCO 68. Unconditional logistic regressions were performed to assess the association between occupations (ever occupied and by duration) and PCa risk, whether all and aggressive, after adjusting for potential confounders. RESULTS: For ≥10 years of employment, we found positive associations with PCa, whether overall and aggressive, among Medical, Dental and Veterinary workers (OR (odds ratios) =5.01 [95% confidence interval] [1.27; 19.77]), Members of the armed forces (OR = 5.14 [0.99; 26.71]) and Fishermen, hunters and related workers (OR = 4.58 [1.33; 15.78]); whether overall and non-aggressive PCa, among Legislative officials and Government administrators (OR = 3.30 [1.10; 9.84]) or Managers (OR = 1.68 [1.18; 2.41]); however a negative association, whether overall and non-aggressive PCa, among Material-Handling and Related Equipment Operators, Dockers and Freight Handlers (OR = 0.40 [0.17; 0.97]). CONCLUSION: Excess PCa risks were observed in the EPICAP study mostly among white collar workers exposed to several factors in their work environment. These emerging associations can be used to lead future research investigating specific occupational exposures.

Adapted dietary inflammatory index and differentiated thyroid carcinoma risk in two French population-based case-control studies.

PURPOSE: Thyroid cancer is the most common endocrine cancer and its etiology is still not well understood. The aim of the present study was to assess the association between an adapted dietary inflammatory index and differentiated thyroid cancer (DTC) risk in two population-based case-control studies (CATHY and YOUNG-THYR) conducted in France. METHODS: These studies included a total of 1321 DTC cases and 1502 controls, for which an adapted dietary inflammatory index (ADII) was computed based on food frequency questionnaires in each study separately. The association between ADII and thyroid cancer risk was assessed using logistic regression models controlling for potential confounders. RESULTS: Higher ADII scores, corresponding to a higher pro-inflammatory potential of the diet, were associated with higher DTC risk (odds ratio (OR) for 1 standard deviation (SD) increase: 1.09, 95% confidence interval (CI): 1.01, 1.18, P: 0.03). Associations were stronger in analyses restricted to women (OR for 1-SD increase: 1.14, 95% CI 1.04, 1.25, P: 0.005), as well as in women with lower education level, current smoking, or high body mass index. CONCLUSION: Our study suggests that a pro-inflammatory diet is associated with an increased risk of DTC, especially when combined with other inflammatory conditions such as tobacco smoking or overweight. Our findings will help better understand the role of diet-induced inflammation in DTC etiology.

A case-control study in France showing that a pro-inflammatory diet is associated with a higher risk of breast cancer.

Dietary regimens promoting inflammatory conditions have been implicated in breast cancer development, but studies on the association between pro-inflammatory diet and breast cancer risk have reported inconsistent results. We investigated the association between the inflammatory potential of diet and breast cancer risk in a case-control study in France including 872 breast cancer cases and 966 population controls. All women completed a food frequency questionnaire that was used to compute a Dietary Inflammatory Index (DII) based on the inflammatory weight of 33 dietary components. The DII ranged from a median of - 3.22 in the lowest quartile (anti-inflammatory) to + 2.96 in the highest quartile (pro-inflammatory). The odds ratio contrasting quartile 4 to quartile 1 was 1.31 (95% CI 1.00, 1.73; p-trend = 0.02). Slightly higher odds ratios were observed in post-menopausal women, particularly those with body mass index > 25 kg/m2 (odds ratio 1.62; 95% CI 0.92, 2.83; p-trend = 0.02), and among ever smokers (odds ratio 1.71; 95% CI 1.11, 2.65; p-trend 0.01). The analyses by breast cancer subtype showed that the DII was associated with breast tumors that expressed either the estrogen (ER) or progesterone (PR) hormone receptors or the Human Epidermal Growth Factor Receptor-2 (HER2), but no association was seen for the triple negative breast tumor subtype. Our results add further evidence that a pro-inflammatory diet is associated with breast cancer risk with possible effect variation according to tumor subtype.

Marital status and prostate cancer incidence: a pooled analysis of 12 case-control studies from the PRACTICAL consortium.

While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case-control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER's summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted.

Role of DNA Repair Variants and Diagnostic Radiology Exams in Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case-Control Studies.

BACKGROUND: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer. METHODS: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case-control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies. RESULTS: The OR/mGy was 1.02 (95% confidence interval, 1.00-1.03). We found significant associations between DTC and rs7164173 in CHD2 (P = 5.79 × 10-5), rs6067822 in NFATc2 (P = 9.26 × 10-5), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses (P = 3.40 × 10-4). CONCLUSIONS: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk. IMPACT: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.

Body mass index trajectories and prostate cancer risk: Results from the EPICAP study.

Elevated body mass index (BMI) has been inconsistently associated with prostate cancer occurrence but it has been suggested that life course adulthood obesity may be associated with an increased risk of prostate cancer. However, few studies have investigated lifetime BMI and prostate cancer risk. We analyzed life course BMI trajectories on prostate cancer risk based on data from the Epidemiological study of Prostate Cancer (EPICAP). We included in our analyses 781 incident prostate cancer cases and 829 controls frequency matched by age. Participants were asked about their weight every decade from age 20 to two years before reference date. BMI trajectories were determined using group-based trajectory modeling to identify groups of men with similar patterns of BMI changes. We identified five BMI trajectories groups. Men with a normal BMI at age 20 developing overweight or obesity during adulthood were at increased risk of aggressive prostate cancer compared to men who maintained a normal BMI. Our results suggest that BMI trajectories resulting in overweight or obesity during adulthood are associated with an increased risk of aggressive prostate cancer, particularly in never smokers, emphasizing the importance of maintaining a healthy BMI throughout adulthood.

Outdoor light at night at residences and breast cancer risk in Canada.

Experimental and epidemiologic studies suggest that light at night (LAN) exposure disrupts circadian rhythm, and this disruption may increase breast cancer risk. We investigated the potential association between residential outdoor LAN and breast cancer risk. A population-based case-control study was conducted in Vancouver, British Columbia and Kingston, Ontario, Canada with incident breast cancer cases, and controls frequency matched by age in the same region. This analysis was restricted to 844 cases and 905 controls who provided lifetime residential histories. Using time-weighted average duration at each home 5-20 years prior to study entry, two measures of cumulative average outdoor LAN were calculated using two satellite data sources. Logistic regression was used to estimate the relationship between outdoor LAN and breast cancer risk, considering interactions for menopausal status and night shift work. We found no association between residential outdoor LAN and breast cancer for either measure of LAN [OR comparing highest vs. lowest tertile (DNB) = 0.95, 95% CI 0.70-1.27]. We also found no association when considering interactions for menopausal status and past/current night work status. These findings were robust to changes to years of residential data considered, residential mobility, and longer exposure windows. Our findings are consistent with studies reporting that outdoor LAN has a small effect or no effect on breast cancer risk.

Role of GSTM1 and GSTT1 genotypes in differentiated thyroid cancer and interaction with lifestyle factors: Results from case-control studies in France and New Caledonia.

BACKGROUND: GSTM1 and GSTT1 are involved in detoxification of xenobiotics, products of oxidative stress and in steroid hormones metabolism. We investigated whether GSTM1 and GSTT1 gene deletion was associated with DTC risk and explored interaction with non-genetic risk factors of DTC. METHODS: The study included 661 DTC cases and 736 controls from two case-control studies conducted in France and New Caledonia. Odds ratios (OR) and their confidence interval (CI) for DTC associated with GST genotypes, alcohol drinking, tobacco smoking, body mass index and hormonal factors were calculated using logistic regression models. RESULTS: Results are presented for Europeans and Melanesians combined, as no heterogeneity between groups was detected. We found that DTC risk increased with obesity and decrease with alcohol drinking. After stratification by gene deletion status, the OR for obesity was 5.75, (95%CI 2.25-14.7) among individuals with GSTT1 and GSTM1-deleted genotype, and 1.26, (95%CI 0.89-1.77) in carriers of both genes (p-interaction = 0.02). The OR for drinking ≥1 glass/week was 0.33 (95%CI 0.15-0.74) in GSTT1-null individuals while it was 1.01 (95%CI 0.67-1.52) in non-null carriers of the gene (p-interaction = 0.01). No interaction between GST genotypes and other non-genetic risk factors was detected. CONCLUSION: GSTM1 and GSTT1 genotypes may modulate the DTC risk associated with BMI and alcohol consumption.

Genome-wide association study of germline variants and breast cancer-specific mortality.

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Breast Cancer and Exposure to Organochlorines in the CECILE Study: Associations with Plasma Levels Measured at the Time of Diagnosis and Estimated during Adolescence.

Exposure to environmental chemicals with hormonal effects, such as organochlorine compounds (OCs), during developmental periods of breast cells may have an impact on the incidence of breast cancer later in life. However, the assessment of exposure to these chemicals that occurred in early life at the time of breast cancer development in adult women is a difficult challenge in epidemiological studies. Plasma levels of the OCs p,p'-dichlorodiphenyl dichloroethene (DDE) and polychlorinated biphenyl congener 153 (PCB153) were measured in 695 cases and 1055 controls of a population-based case-control study conducted in France (CECILE study). Based on these values, we used a physiologically-based pharmacokinetic (PBPK) model to estimate PCB153 levels at age 11⁻20 years when the women were adolescents. Overall, there was no clear association between breast cancer risk and measured levels of DDE and PCB153 at the time of diagnosis, but there was a trend of decreasing odds ratios of breast cancer with increasing DDE and PCB153 levels in women aged 50 years and over. The PBPK model revealed that PCB153 concentrations estimated during adolescence were highest in the youngest women born after 1960 who reached adolescence at a time when environmental contamination was maximum, and very low in the oldest women who attained adolescence before the contamination peak. Negative associations between breast cancer and PCB153 estimates during adolescence were also found. The negative associations between DDE and PCB153 levels measured at the time of diagnosis or estimated during adolescence in our study were unexplained. Further investigations are needed to clarify whether this finding is real or related to study artifacts. However, this study suggests that using PBPK models in epidemiological studies to back-estimate OC exposures during early life stages may be useful to address critical questions on cancer development.

Association of breast cancer risk with polymorphisms in genes involved in the metabolism of xenobiotics and interaction with tobacco smoking: A gene-set analysis.

Single nucleotide polymorphisms (SNPs) in genes involved in xenobiotics metabolism (XM) are suspected to play a role in breast cancer risk. However, previous findings based on a SNP by SNP approach need to be replicated taking into account the combined effects of multiple SNPs. We used a gene-set analysis method to study the association between breast cancer risk and genetic variation in XM genes (seen as a set of SNPs) and in the XM pathway (seen as a set of genes). We also studied the interaction between variants in XM genes and tobacco smoking. The analysis was conducted in a case-control study of 1,125 cases and 1,172 controls. Using a dedicated chip, genotyping data of 585 SNPs in 68 XM genes were available. Genetic variation in the whole XM pathway was significantly associated with premenopausal breast cancer risk (p = 0.008). This association was mainly driven by genetic variation in NAT2, CYP2C18, CYP2C19, AKR1C2 and ALDH1A3. The association between the XM gene pathway and breast cancer was observed among current and previous smokers, but not among never smokers (p = 0.013 for interaction between XM genes and tobacco smoking status). The association with breast cancer risk indicates that XM genes variants may play a role in breast carcinogenesis through their detoxification function of environmental pollutants, such as those contained in tobacco smoke.