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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.

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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.

Background: 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. Methods: 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-8 as genome-wide significant, and p-values-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: 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-values5. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) 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. Conclusions: 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.

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.

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 (

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).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.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.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.

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.

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.

Background: 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. Methods: 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 age-matched 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. Results: 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 >25kg/m 2 (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. Conclusion: Our results add further evidence that a pro-inflammatory diet is associated with breast cancer risk with possible effect variation according to tumor subtype.

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.

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.

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., The influence of body weight during lifetime on PCa risk remains largely ununderstood and has been poorly investigated. Our findings suggest that elevated BMI during adulthood resulting in overweight or obesity is associated with an increased risk of aggressive PCa, emphasizing the importance of maintaining a healthy BMI throughout adulthood.

Night shift work has been suspected to increase breast cancer risk but epidemiological studies have been inconsistent due to heterogeneous assessment of exposure to night work. To overcome this limitation, we pooled data of five population-based case-control studies from Australia, Canada, France, Germany, and Spain into a single harmonized dataset using a common definition of night work including 6093 breast cancer cases and 6933 population controls. The odds ratio for breast cancer in women who ever worked at night for at least 3 h between midnight and 5 a.m. as compared to never night workers was 1.12 (95% CI 1.00-1.25). Among pre-menopausal women, this odds ratio was 1.26 [1.06-1.51], increasing to 1.36 [1.07-1.74] for night shifts ≥ 10 h, 1.80 [1.20-2.71] for work ≥ 3 nights/week, and 2.55 [1.03-6.30] for both duration of night work ≥ 10 years and exposure intensity ≥ 3 nights/week. Breast cancer risk in pre-menopausal women was higher in current or recent night workers (OR = 1.41 [1.06-1.88]) than in those who had stopped night work more than 2 years ago. Breast cancer in post-menopausal women was not associated with night work whatever the exposure metric. The increase in risk was restricted to ER+ tumors, particularly those who were both ER+ and HER2+ . These results support the hypothesis that night shift work increases the risk of breast cancer in pre-menopausal women, particularly those with high intensity and long duration of exposure. Risk difference between pre- and post-menopausal women deserves further scrutiny.

Background Breast cancer is the leading cause of cancer death in women worldwide. Besides reproductive and hormonal breast cancer risk factors which are hardly modifiable, the identification of occupational or environmental risk factors may be a key to prevention. It has been suggested that exposure to organic solvents in the workplace may play a role in the etiology of breast cancer. However, most epidemiological studies on solvents in female breast cancer have reported inconsistent results. Methods We examined the risk of breast cancer related to lifetime exposure to chlorinated, petroleum-based and oxygenated solvents in the CECILE study, a large population-based case-control study carried out in France (2005–2007). 1230 women with breast cancer and 1315 population controls were included. Data collected included sociodemographic characteristics, medical and family history, anthropometric measurements, reproductive history, lifestyle habits, and lifetime occupational history. All jobs were coded using the International Standard Classification of Occupations (ISCO 1968) and the Classification of Activities in the European Community (NACE 1991). Exposure to five chlorinated, five petroleum and five oxygenated solvents was assessed using job-exposure matrices, which assigned indices of exposure (probability, frequency and intensity) for each job. A Cumulative Exposure Score (CES) taking into account probability, frequency, intensity and duration of exposure was calculated for each subject. Odds ratio (ORs) and their 95% confidence intervals (95% CI) were estimated using unconditional logistic regression adjusting for potential confounders. Analyses were stratified by the menopausal status. Results Significantly increased ORs were found in premenopausal women with high probability of exposure to alcohols (1.50; 1.05–2.14) and diethyl ether (1.97; 1.00–3.88). Premenopausal women with the highest CES of oxygenated solvents had an OR of 1.70 (1.09–2.64) (OR=1.67; 1.10–2.52 for alcohols, 1.80; 0.95–3.42 for diethyl ether); the highest CES of chlorinated solvents was associated with an OR of 2.14 (0.86–5.30). In premenopausal women, a duration of exposure to oxygenated solvents ≥25 years with a probability of exposure ≥80% significantly increased the risk of breast cancer (OR=2.62; 1.27–5.40 for all solvents, 2.72; 1.30–5.70 for alcohols, and 2.79; 0.67–11.6 for diethyl ether). No association was observed for oxygenated, petroleum-based or chlorinated solvents in postmenopausal women. Conclusion These findings suggest a role of occupational exposure to oxygenated solvents, notably to alcohols and diethyl ether, in the occurrence of breast cancer in premenopausal women. Our results highlight the importance of timing and duration of exposure for the study of occupational exposure to solvents in breast cancer risk.

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.

L’hypothese d’un risque eleve de cancer du sein chez les travailleurs de nuit a fait l’objet de plusieurs etudes epidemiologiques depuis une vingtaine d’annees, mais les resultats contradictoires ont donne lieu a d’intenses debats dans la communaute scientifique. Il existe en realite une grande diversite dans la definition du travail de nuit et dans la quantification de l’exposition pouvant expliquer les resultats divergents. Nous avons constitue une base de donnees harmonisee sur le travail de nuit et le cancer du sein a partir des donnees individuelles de 5 grandes etudes epidemiologiques conduites en Allemagne, Espagne, France, Canada, et Australie, comportant 6093 cas de cancer du sein et 6933 femmes temoins ayant declare au total 54,000 emplois sur l’ensemble de leur carriere professionnelle. Sur la base d’une definition commune du travail de nuit (au moins 3 heures de travail entre minuit et 5 heures du matin), le risque de cancer du sein etait augmente de 12 % chez les femmes ayant travaille de nuit (odds ratio OR = 1,12 ; IC95 % 1,00–1,25). Le risque de cancer du sein etait plus eleve chez les femmes pre-menopausees (OR = 1,26 ; IC95 % 1,06–1,51), celles qui travaillaient au moins 3 nuits par semaine (OR = 1,80 ; IC95 % 1,20–2,71), ou celles dont la duree du poste de nuit etait de 10 heures ou plus (OR = 1,36 ; IC95 % 1,07–1,74). Chez les femmes exposees, le risque de cancer du sein diminuait avec le nombre d’annees depuis l’arret du travail de nuit. Cette etude a permis des avancees tres significatives dans les connaissances des effets cancerogenes du travail de nuit, et a constitue un element determinant dans la recente monographie du Centre International de Recherche sur le Cancer de 2019 ou le travail de nuit a ete classe en cancerogene probable. L’importance de la surveillance du cancer du sein dans les groupes professionnels concernes par le travail de nuit doit etre soulignee.

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.

In 2007, IARC classified ”shift work that involves circadian disruption” as probably carcinogenic to humans. To date, the evidence that night shift work increases the risk of breast cancer remains limited, partly because exposure to night work is defined differently across studies. To overcome this limitation, we created a single harmonised dataset using a common definition of night work from 5 major population-based case-control studies on breast cancer in Australia, Canada, France, Germany, and Spain. The dataset included 6000 breast cancer cases and 7000 population controls. Any job held during work history that included at least 3 hours between midnight and 5 am was classified as night work. Lifetime duration of night work, frequency (nights/week), and night shift length (hours) were used as the main exposure variables. In pre-menopausal women who ever worked at night the pooled OR was 1.23 [1.03–1.47]. The OR increased to 1.75 [1.17–2.62] in premenopausal women who worked at least 3 nights/week and 1.33 [1.05–1.70] for night shifts≥10 hours. The OR did not increase with the number of years of night work, but women who worked ≥3 nights/week for ≥10 years had an OR of 2.58 [1.05–6.36]. No association emerged from the data in post-menopausal women. No statistically significant heterogeneity between studies was observed. Our results support the hypothesis that night work increases breast cancer risk, particularly in pre-menopausal who worked at least 3 nights per week. The absence of an association in post-menopausal women needs further scrutiny.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint )

Item does not contain fulltext Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G x E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 x 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 x 10(-05)). Our findings confirm comparable power of the recent methods for detecting G x E interaction and the utility of using G x E interaction analyses to identify new susceptibility loci.

Background In the context of a possible role of chronic inflammation in cancer risk, our objective was to investigate breast cancer risk in relation to the use of selective COX2 inhibitors and other non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, and to explore interactions of NSAIDs with COX2 genetic polymorphisms. Methods We conducted a population-based case-control study in France on breast cancer risk factors. Data on NSAID use were obtained in 871 cases and 915 controls using a standardized questionnaire, and 7 single nucleotide polymorphisms in the COX2 gene were genotyped in 811 cases and 829 controls. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated using unconditional logistic regression models. Results We found an inverse association between breast cancer and NSAID use (OR = 0.80, 95% CI: 0.66–0.97), which was stronger for COX2 selective inhibitors (OR = 0.55, 95% CI: 0.35–0.86). Associations were more pronounced in salicylate non-users and overweight women. The SNP rs5275 in COX2 genes was associated with breast cancer (P = 0.01) and a significant interaction between rs5275 and NSAID use was observed (P for interaction 0.02). Conclusion Our results confirm an inverse association between NSAID use and breast cancer and highlight the role of selective COX2 inhibitors. Polymorphisms of the COX2 gene may modify the risk of breast cancer associated with NSAID use.

Background Overweight and weight gain throughout adult life have been associated with increased risk of breast cancer after the menopause. However the role of body weight at a young age and of the timing of weight gain over the lifetime in postmenopausal breast cancer is not well documented. Methods We conducted a population-based case-control study on breast cancer in France that included 739 cases and 815 population controls in postmenopausal women. Height, weight at age 20, 40 and 50 as well as weight one year before diagnosis were obtained during in-person interviews. Results No association between body mass index at the age of 20 years and breast cancer after the menopause was detected. However, we found that postmenopausal breast cancer was associated with weight gain between ages 40 and 50 years (OR per 5 kg/m2 increase in BMI: 1.45 [95%ci 1.06−1.98]). The increased risk of breast cancer associated with weight gain was more consistent in leaner women at age 20, in older postmenopausal women (>65 years), and in women who did not use menopausal hormone therapy. Conclusions These findings point to the importance of controlling for weight gain in middle aged-women. The role of low body weight in young adulthood in breast cancer risk after the menopause should be further scrutinized. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2793-0) contains supplementary material, which is available to authorized users.

Shift work involving circadian disruption was classified as probably carcinogenic (group 2A) by IARC in 2007 based on sufficient evidence in experimental animals and limited evidence in humans. To date, the evidence of an association between night shift work and breast cancer risk available from epidemiological studies remains limited, mainly because of the heterogeneity of exposure assessment methods that were used in these studies. Several meta-analyses have been conducted but could not adequately harmonise exposure assessment of shift work. To overcome this limitation, we are conducting a combined analysis of the major population-based case–control studies on breast cancer using a common definition of night work to characterise exposure. We will combine individual data from population-based studies with complete job histories and detailed night work schedules conducted in France, Germany, Spain, Canada, and Australia, including approximately 5000 breast cancer cases and 5000 controls. Breast cancer risk will be investigated in relation to a common definition of night work across the studies (e.g. at least 3 hours between midnight and 5 am), using exposure duration (in years), intensity (number of nights per month), and number of consecutive nights as the main exposure variables. Specific exposure windows during lifetime will also be considered. Analyses will also be conducted after stratification on occupation (healthcare, flight attendants, etc.) to assess the effect of occupation-specific patterns of night work schedule on breast cancer risk. We will also study the association of night work with breast cancer subtypes (ER, PR and HER2 receptor status). Sensitivity analyses using varying definitions of night work schedules will be conducted. Preliminary results will be presented at the meeting. This re-analysis of epidemiological data will provide further insight on the role of night work on breast cancer based on a large epidemiological dataset with high statistical power.

Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed

Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women.

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

Introduction Breast cancer is the leading cause of cancer death in women worldwide. Its incidence is only partially explained by well-established risk factors related to hormones and reproduction. It has been suggested that exposure to organic solvents in the workplace may play a role in the etiology of breast cancer, but epidemiological studies on these occupational exposures in female breast cancer did not assess exposure to specific solvents and reported inconsistent results. Methods We examined the risk of breast cancer-related to lifetime exposure to organic solvents in a large population-based case-control study carried out in France between 2005 and 2008; 1230 women newly diagnosed for a breast cancer and 1315 population controls were included. A standardized questionnaire was administered during in-person interviews by trained interviewers to obtain information on socio-demographic characteristics, medical and family history, anthropometric measurements, reproductive history, tobacco and alcohol consumption, diet, and lifetime occupational history. All jobs held during occupational history were coded using the International Standard Classification of Occupations (ISCO 1968) and the Classification of Activities in the European Community (NACE 1991). Exposure to chlorinated (n = 4), petroleum (n = 5) and oxygenated (n = 5) solvents was assessed using a detailed job-exposure matrix (JEM) developed by the French National Agency for Public Health. Each job held was assigned indices of exposure probability, frequency and intensity. A Cumulative Exposure Score (CES) was calculated for each subject as the sum of the products of exposure probability, frequency and intensity, and duration for each job held over the entire occupational life. Odds ratio (ORs) and their 95% confidence intervals (95% CI) were estimated using unconditional logistic regression adjusting for potential confounders. Results The highest lifetime exposure prevalence was found for alcoholic solvents (41.8% of the cases and 41.4% of the controls); white spirit (8.3% of the cases and 10.2% of the controls); and trichloroethylene (10.7% of the cases and 11.8% of the controls). Compared to non-exposed subjects, women in the highest cumulative exposure quartile for alcoholic solvents had an OR of 1.17 (95% CI = 0.90–1.52). This OR increased to 1.61 (95% CI = 1.06–2.46) in premenopausal women. Exposure to ethylene glycol was also associated with an increased OR of 1.36 (95% CI = 0.93–1.97) in premenopausal women. No association was observed for other oxygenated solvents, petroleum solvents or chlorinated solvents. Conclusions These findings suggest a role of occupational exposure to oxygenated solvents, notably to alcohols, in the occurrence of breast cancer. Further studies conducted in cohorts of women with high prevalence of exposure to solvents are needed to confirm these results.

Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5 216 302 women, including 113 178 events. In a consortium with individual-level data from 46 325 case patients and 42 482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16 003 case patients and 41 335 control subjects. Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10 cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10 cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5 × 10-8. Conclusions: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.

Objectifs Le cancer du sein est le plus frequent des cancers chez la femme, et son incidence est expliquee partiellement par des facteurs de risque bien etablis comme les facteurs reproductifs, hormonaux ou genetiques. Nous examinons ici le role des expositions professionnelles aux solvants oxygenes dans le risque de cancer du sein. Methodes Nous utilisons ici les donnees d’une etude cas-temoins comportant des informations detaillees sur l’historique professionnel de 1230 cas de cancer du sein feminin et 1315 temoins de population generale recueillies a l’aide d’un questionnaire standardise. Les expositions a 5 solvants oxygenes ont ete evaluees par l’intermediaire d’une matrice emplois-exposition. Les odds ratios (OR) et leurs intervalles de confiance a 95 % (IC 95 %), ajustes sur les facteurs de confusion potentiels ont ete estimes a l’aide de regressions logistiques. Resultats Parmi les femmes de l’etude, 44,1 % ont pu etre exposees a au moins un solvant oxygene au cours de leur carriere (41,6 % aux alcools, 11,7 % a l’ether ethylique, 9,2 % aux cetones-esters, 0,7 % au tetrahydrofurane et 0,3 % a l’ethylene glycol). Apres ajustement, l’exposition aux alcools etait associee avec un risque accru de cancer du sein chez les femmes en pre-menopause (OR = 1,61, IC 95 % = 1,06–2,46). Aucune association statistiquement significative n’etait observee pour les autres solvants oxygenes. Conclusion Nos resultats mettent en evidence un possible role de l’exposition aux solvants alcool dans le cancer du sein, notamment chez les femmes non menopausees.

Night shift work has been associated with an increased risk of breast cancer pointing to a role of circadian disruption. We investigated the role of circadian clock gene polymorphisms and their interaction with nightwork in breast cancer risk in a population-based case–control study in France including 1126 breast cancer cases and 1174 controls. We estimated breast cancer risk associated with each of the 577 single nucleotide polymorphisms (SNPs) in 23 circadian clock genes. We also used a gene- and pathway-based approach to investigate the overall effect on breast cancer of circadian clock gene variants that might not be detected in analyses based on individual SNPs. Interactions with nightwork were tested at the SNP, gene, and pathway levels. We found that two SNPs inRORA(rs1482057 and rs12914272) were associated with breast cancer in the whole sample and among postmenopausal women. In this subpopulation, we also reported an association with rs11932595 inCLOCK, and withCLOCK,RORA, andNPAS2in the analyses at the gene level. Breast cancer risk in postmenopausal women was also associated with overall genetic variation in the circadian gene pathway (P=0.04), but this association was not detected in premenopausal women. There was some evidence of an interaction betweenPER1and nightwork in breast cancer in the whole sample (P=0.024), although the effect was not statistically significant after correcting for multiple testing (P=0.452). Our results support the hypothesis that circadian clock gene variants modulate breast cancer risk.

Contains fulltext : 118401.pdf (Publisher’s version ) (Open Access) Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 x 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 x 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of /= 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 x 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case–control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showingPvalues for interaction (Pint) −3were selected for replication using pooled case–control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combinedPint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 nearPOMP(combinedPint≤8.9×10−6), two SNPs inSLC25A21(combinedPint≤4.8×10−5), and three SNPs inPLCG2(combinedPint≤4.5×10−5). The association between lobular BC risk was potentially modified by one SNP inTMEFF2(combinedPint≤2.7×10−5), one SNP inCD80(combinedPint≤8.2×10−6), three SNPs on chr17 nearTMEM132E(combinedPint≤2.2×10−6), and two SNPs on chr18 nearSLC25A52(combinedPint≤4.6×10−5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.