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Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow‐up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri‐menopausal women, 111 in post‐menopausal women, and 70 in men) and 706 cancer‐free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre‐menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96–2.92, ptrend =.06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96–3.30, ptrend =.06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28–1.05, ptrend =.07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post‐menopausal women and men but may suggest an involvement of altered sex steroid production in pre‐menopausal women. [ABSTRACT FROM AUTHOR]

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02–1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04–1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09–1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation. [ABSTRACT FROM AUTHOR]

Background: The Mediterranean diet has been associated with lower risk of breast cancer (BC) but evidence from prospective studies on the role of Mediterranean diet on BC survival remains sparse and conflicting. We aimed to investigate whether adherence to Mediterranean diet prior to diagnosis is associated with overall and BC-specific mortality. Methods: A total of 13,270 incident breast cancer cases were identified from an initial sample of 318,686 women in 9 countries from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Adherence to Mediterranean diet was estimated through the adapted relative Mediterranean diet (arMED), a 16-point score that includes 8 key components of the Mediterranean diet and excludes alcohol. The degree of adherence to arMED was classified as low (score 0–5), medium (score 6–8), and high (score 9–16). Multivariable Cox proportional hazards models were used to analyze the association between the arMED score and overall mortality, and Fine-Gray competing risks models were applied for BC-specific mortality. Results: After a mean follow-up of 8.6 years from diagnosis, 2340 women died, including 1475 from breast cancer. Among all BC survivors, low compared to medium adherence to arMED score was associated with a 13% higher risk of all-cause mortality (HR 1.13, 95%CI 1.01–1.26). High compared to medium adherence to arMED showed a non-statistically significant association (HR 0.94; 95% CI 0.84–1.05). With no statistically significant departures from linearity, on a continuous scale, a 3-unit increase in the arMED score was associated with an 8% reduced risk of overall mortality (HR3-unit 0.92, 95% CI: 0.87–0.97). This result sustained when restricted to postmenopausal women and was stronger among metastatic BC cases (HR3-unit 0.81, 95% CI: 0.72–0.91). Conclusions: Consuming a Mediterranean diet before BC diagnosis may improve long-term prognosis, particularly after menopause and in cases of metastatic breast cancer. Well-designed dietary interventions are needed to confirm these findings and define specific dietary recommendations. [ABSTRACT FROM AUTHOR]

Several R packages have been developed to study cross-phenotypes associations (or pleiotropy) at the SNP-level, based on summary statistics data from genome-wide association studies (GWAS). However, none of them allow for consideration of the underlying group structure of the data. We developed an R package, entitled GCPBayes (Group level Bayesian Meta-Analysis for Studying Cross-Phenotype Genetic Associations), introduced by Baghfalaki et al. (2021), that implements continuous and Dirac spike priors for group selection, and also a Bayesian sparse group selection approach with hierarchical spike and slab priors, to select important variables at the group level and within the groups. The methods use summary statistics data from association studies or individual level data as inputs, and perform Bayesian meta-analysis approaches across multiple phenotypes to detect pleiotropy at both group-level (e.g., at the gene or pathway level) and within group (e.g., at the SNP level). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome‐wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population‐based case‐control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray‐500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid‐stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations. What's new? Differentiated thyroid carcinoma (DTC) has a strong genetic component, and Pacific Islanders have a particularly high incidence of the disease. Here, the authors conducted a genome‐wide association study (GWAS) in a mixed population including individuals of European and Pacific Islander ancestry. The study drew from the EPITHYR consortium, a collection of 2000 DTC cases and age‐matched controls. The analysis confirmed 5 previously known susceptibility loci and identified 2 new ones. Three of these loci were more prevalent among Pacific Islanders. More studies are needed to fully account for the rate of DTC in that population. [ABSTRACT FROM AUTHOR]

Single‐nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome‐wide association studies involving mostly unselected population‐based case‐control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC‐prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP‐level analysis using index cases and controls, we performed pedigree‐based association tests to capture transmission information in the sibships. We also performed gene‐ and pathway‐level analyses to maximize the power to detect associations with lower‐frequency SNPs or those with modest effect sizes. While SNP‐level analyses identified 18 loci, gene‐level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the "index case‐control" analysis, we built pathway‐derived polygenic risk scores (PRS) and assessed their performance in the population‐based CECILE study and in a data set composed of GENESIS‐affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP‐level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models. What's new? Genetic studies have identified more than 180 single‐nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, but these studies are reaching their limits. Here, the authors evaluated SNPs in the iCOGS genotyping array using a multilevel approach, including single variant, gene, and pathway analyses. They measured the contribution of the SNPs to breast cancer in patients who have a sister with breast cancer but do not carry a BRCA1/2 mutation. They showed that a pathway‐derived polygenic risk score performed poorly in the general population, and that the best predictive model must include family history. [ABSTRACT FROM AUTHOR]

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross‐validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10‐fold cross‐validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross‐validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47‐4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65‐0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans. What's new? Polygenic models can provide personalized estimates of cancer risk. However, Africans are a population generally under‐served in genome‐wide studies. In this report, the authors used machine learning to identify three SNPs that significantly improved the performance of an established polygenic‐hazard model of prostate‐cancer risk vs age at diagnosis, specifically tailored to men of African genetic ancestry. Inclusion of these SNPs improved the performance of this novel 'PHS46+African' score by as much as 79% compared to the original model, to levels comparable with Europeans. [ABSTRACT FROM AUTHOR]

Over the past two decades, several studies have attempted to understand the hypothesis that disrupting the circadian rhythm may promote the development of cancer. Some have suggested that night work and some circadian genes polymorphisms are associated with cancer, including prostate cancer. Our study aims to test the hypothesis that prostate cancer risk among night workers may be modulated by genetic polymorphisms in the circadian pathway genes based on data from the EPICAP study, a population‐based case‐control study including 1511 men (732 cases/779 controls) with genotyped data. We estimated odds ratio (ORs) and P values of the association between prostate cancer and circadian gene variants using logistic regression models. We tested the interaction between circadian genes variants and night work indicators that were significantly associated with prostate cancer at pathway, gene and SNP levels. Analyses were also stratified by each of these night work indicators and by cancer aggressiveness. The circadian pathway was significantly associated with aggressive prostate cancer among night workers (P =.004), particularly for men who worked at night for <20 years (P =.0002) and those who performed long night shift (>10 hours, P =.001). At the gene level, we observed among night workers significant associations between aggressive prostate cancer and ARNTL, NPAS2 and RORA. At the SNP‐level, no significant association was observed. Our findings provide some clues of a potential modulating effect of circadian genes in the relationship between night work and prostate cancer. Further investigation is warranted to confirm these findings and to better elucidate the biological pathways involved. What's new?: Night shift work that disrupts circadian rhythm is a probable carcinogen in humans. Moreover, certain circadian gene polymorphisms have been linked to cancer. In this investigation of night shift work, circadian pathway, and prostate cancer, circadian genes were significantly associated with aggressive prostate malignancy, especially in long‐term night shift workers and those who worked more hours at night. Aggressive prostate cancer was linked in particular to the circadian genes ARNTL, NPAS2, and RORA, though no associations were detected for specific polymorphisms. The findings offer new insight into interactions between circadian genes, night shift work, and prostate cancer. [ABSTRACT FROM AUTHOR]

Polyphenols are bioactive compounds with several anticarcinogenic activities; however, human data regarding associations with thyroid cancer (TC) is still negligible. Our aim was to evaluate the association between intakes of total, classes and subclasses of polyphenols and risk of differentiated TC and its main subtypes, papillary and follicular, in a European population. The European Prospective Investigation into Cancer and Nutrition cohort included 476,108 men and women from 10 European countries. During a mean follow‐up of 14 years, there were 748 incident differentiated TC cases, including 601 papillary and 109 follicular tumors. Polyphenol intake was estimated at baseline using validated center/country‐specific dietary questionnaires and the Phenol‐Explorer database. In multivariable‐adjusted Cox regression models, no association between total polyphenol and the risks of overall differentiated TC (HRQ4 vs. Q1 = 0.99, 95% confidence interval [CI] 0.77–1.29), papillary (HRQ4 vs. Q1 = 1.06, 95% CI 0.80–1.41) or follicular TC (HRQ4 vs. Q1 = 1.10, 95% CI 0.55–2.22) were found. No associations were observed either for flavonoids, phenolic acids or the rest of classes and subclasses of polyphenols. After stratification by body mass index (BMI), an inverse association between the intake of polyphenols (p‐trend = 0.019) and phenolic acids (p‐trend = 0.007) and differentiated TC risk in subjects with BMI ≥ 25 was observed. In conclusion, our study showed no associations between dietary polyphenol intake and differentiated TC risk; although further studies are warranted to investigate the potential protective associations in overweight and obese individuals. What's new? Polyphenols are secondary plant metabolites with health protective properties but whether a diet rich in polyphenols protects from thyroid cancer has not been conclusively explored. In this large prospective study, no associations were observed between dietary polyphenol intake and differentiated thyroid cancer risk. The authors recommend further studies to investigate potential associations specifically in overweight and obese individuals. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Circadian rhythms regulate several physiological functions and genes controlling the circadian rhythm were found to regulate cell proliferation, cell cycle and apoptosis. Few studies have investigated the role of those circadian genes in prostate cancer occurrence. We aim to investigate the relationship between circadian genes polymorphisms and prostate cancer risk based on data from the EPICAP study, a population‐based case–control study including 1,515 men (732 cases / 783 controls) with genotyped data. Odds Ratios (ORs) for association between prostate cancer and circadian gene variants were estimated for each of the 872 single nucleotide polymorphisms (SNPs) in 31 circadian clock genes. We also used a gene‐based and pathway‐based approach with a focus on the pathway including 9 core circadian genes. Separate analyses were conducted by prostate cancer aggressiveness. The core‐circadian pathway (p = 0.0006) was significantly associated to prostate cancer, for either low (p = 0.002) or high (p = 0.01) grade tumor. At the gene level, we observed significant associations between all prostate cancer and NPAS2 and PER1 after correcting for multiple testing, while only RORA was significant for aggressive tumors. At the SNP‐level, no significant association was observed. Our findings provide additional evidence of a potential link between genetic variants in circadian genes and prostate cancer risk. Further investigation is warranted to confirm these findings and to better understand the biological pathways involved. What's new? Since the publication of the International Agency for Research on Cancer Monograph that classified shift work involving circadian disruption as probably carcinogenic to humans, few epidemiological studies have investigated the role of circadian genes in cancer, including prostate cancer. Based on data from a population‐based case‐control study including 1,515 men with genotyped data, here the authors observed an association between polymorphisms in the circadian pathway genes and prostate cancer, using a pathway‐based approach. This association was more pronounced when considering the 9 core genes of the pathway. The findings support a role of the circadian genes in prostate cancer carcinogenesis. [ABSTRACT FROM AUTHOR]

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. What's new? While environmental chemicals are risk factors for breast cancer, little is known about whether their role in cancer etiology is influenced by variations in genes involved in carcinogen breakdown via xenobiotic metabolism (XM). To investigate this question, the authors of the present study analyzed interactions between XM genes and tobacco smoking among breast cancer patients. Among ever‐smokers, single nucleotide polymorphisms in XM genes were associated with premenopausal breast cancer. The association was absent among never smokers. The authors conclude that XM gene variants likely modulate breast cancer risk associated with exposure to tobacco smoke, which contains thousands of toxic chemicals. [ABSTRACT FROM AUTHOR]

Background: Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors.Methods: Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status.Results: The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction = 0.009), adult height (P-interaction = 0.025) and current use of combined MHT (P-interaction = 0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P = 0.013 for global and 0.18 for tail-based tests).Conclusions: The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease. [ABSTRACT FROM AUTHOR]

Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER-) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene-environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67-0.88, pint = 1.8 × 10−4). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16-1.59, pint = 1.9 × 10−5) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21-rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12-1.43, pint =1.8 × 10−4) and between 8q23-rs13267382 and age at first full-term pregnancy (ORint = 0.89, 95% CI: 0.83-0.95, pint = 5.2 × 10−4). While these results do not suggest any strong gene-environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed. [ABSTRACT FROM AUTHOR]

Exceptionally high incidence rates of thyroid cancer have been reported in New Caledonia, particularly in Melanesian women. To clarify the reasons of this elevated incidence, we conducted a countrywide population-based case-control study in the multiethnic population of Caledonian women. The study included 293 cases of thyroid cancer and 354 population controls. Based on a food frequency questionnaire, we investigated the role in thyroid cancer of food items rich in iodine-such as seafood-and of vegetables containing goitrogens-such as cruciferous vegetables. A measure of total daily iodine intake based on a food composition table was also used. Our findings provided little support for an association between thyroid cancer and consumption of fish and seafood. We found that high consumption of cruciferous vegetables was associated with thyroid cancer among women with low iodine intake (OR = 1.86; 95% CI: 1.01-3.43 for iodine intake <96 microg/day). The high consumption of cruciferous vegetables among Melanesian women, a group with mild iodine deficiency, may contribute to explain the exceptionally high incidence of thyroid cancer in this group. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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) <1.1 × 10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10−4), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10−5), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10−4). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. [ABSTRACT FROM AUTHOR]

Night shiftwork has been associatedwith 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. Interactionswith nightwork were tested at the SNP, gene, and pathway levels. We found that two SNPs in RORA (rs1482057 and rs12914272) were associated with breast cancer in thewhole sample and among postmenopausalwomen. In this subpopulation, we also reported an association with rs11932595 in CLOCK, andwith CLOCK, RORA, and NPAS2 in the analyses at the gene level. Breast cancer riskinpostmenopausalwomenwas alsoassociatedwith overall genetic variation in the circadian gene pathway (PZ0.04), but this association was not detected in premenopausalwomen. There was some evidence of an interaction between PER1 and nightwork in breast cancer in the whole sample (PZ0.024), although the effect was not statistically significant after correcting for multiple testing (PZ0.452). Our results support the hypothesis that circadian clock gene variants modulate breast cancer risk. [ABSTRACT FROM AUTHOR]

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10 for effect modification of current MHT use. The most significant interaction was observed for rs6707272 ( P = 3 × 10) on chromosome 2 but was not replicated in the BCAC studies ( P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women. [ABSTRACT FROM AUTHOR]

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 perallele 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 and 1.45 (1.14-1.85) in those who drank ≥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. [ABSTRACT FROM AUTHOR]

Night work involving disruption of circadian rhythm was suggested as a possible cause of breast cancer. We examined the role of night work in a large population-based case-control study carried out in France between 2005 and 2008. Lifetime occupational history including work schedules of each night work period was elicited in 1,232 cases of breast cancer and 1,317 population controls. Thirteen percent of the cases and 11% of the controls had ever worked on night shifts (OR = 1.27 [95% confidence interval = 0.99-1.64]). Odds ratios were 1.35 [1.01-1.80] in women who worked on overnight shifts, 1.40 [1.01-1.92] in women who had worked at night for 4.5 or more years, and 1.43 [1.01-2.03] in those who worked less than three nights per week on average. The odds ratio was 1.95 [1.13-3.35] in women employed in night work for >4 years before their first full-term pregnancy, a period where mammary gland cells are incompletely differentiated and possibly more susceptible to circadian disruption effects. Our results support the hypothesis that night work plays a role in breast cancer, particularly in women who started working at night before first full-term pregnancy. [ABSTRACT FROM AUTHOR]

Purpose: Exceptionally high incidence rates of thyroid cancer have been observed in New Caledonia, particularly in Melanesian women, but familial aggregation of thyroid diseases in this population is unknown. We study the association between family history of malignant or benign thyroid diseases and non-medullary thyroid cancer in this country. Methods: We conducted a population-based case-control study including 332 cases with papillary or follicular carcinoma diagnosed in 1993-1999 and 412 controls, matched by sex and 5-year age-group. Results: Thyroid cancer was associated with a history of thyroid cancer in first-degree relatives (odds ratio (OR), 3.2; 95 % CI, 1.6-6.2) and with a family history of multinodular goiter (OR, 3.6; 95 % CI, 1.9-7.0). The ORs did not change by age at diagnosis and with the number of affected relatives. The study provides evidence that the familial component of thyroid cancer is particularly strong in men. Thyroid cancer was not associated with a family history of thyroid diseases in Melanesians from the Loyalty Islands, the area with the highest incidence rates for thyroid cancer, possibly indicating a high frequency of genetic susceptibility variants and lack of genetic variation in this population subgroup. Conclusion: Overall our findings confirm an elevated risk of thyroid cancer in individuals with a family history of malignant or benign thyroid diseases, particularly in Melanesians where familial aggregation of thyroid cancer had never been investigated before. The study of genetic variants in candidate susceptibility genes for thyroid cancer may help clarifying the absence of an association in the subgroup of Melanesians from the Loyalty Islands. [ABSTRACT FROM AUTHOR]

Background It has been suggested that certain occupational exposures may play a role in breast cancer etiology. The recognition of high-risk occupations may give clues about potential mammary carcinogens in the work place. Methods We conducted a population-based case-control study in France including 1,230 breast cancer cases and 1,315 population controls with detailed information on lifetime work history. Odds ratios for women ever employed in an occupation or industry were adjusted for well-established risk factors for breast cancer. Results Adjusted odds ratios were marginally increased in some white-collar occupations, as well as in textile workers (2.4; 95% CI [0.9-6.0]), rubber and plastics product makers (1.8; 95% CI [0.9-3.5]), and in women employed for more than 10 years as nurses (1.4; 95% CI [0.9-2.1]) and as tailors/dressmakers (1.5; 95% CI [0.9-2.6]). The incidence of breast cancer was increased among women employed in the manufacture of chemicals, of non-metallic mineral products, and decreased among women in agriculture. Conclusions These findings suggest a possible role of occupational exposures in breast cancer, including night-shift work, solvents and endocrine disrupting chemicals and require further studies with detailed assessment of occupational exposures. [ABSTRACT FROM AUTHOR]

Exceptionally high incidence rates of thyroid cancer have been reported for Melanesian women in New Caledonia (South Pacific). To investigate the occurrence of thyroid cancer in that country and to clarify the role of goiter and hormonal factors in that disease in women, a countrywide population-based case-control study was conducted in 1993–1999. The study included 293 cases, identified through pathology registers and whose thyroid cancer was verified histologically, and 354 population controls. Thyroid cancer was associated with goiter, age at menarche, irregular menstruation, and hysterectomy. There was a dose-response trend with number of full-term pregnancies (p = 0.01), with an odds ratio of 2.2 (95% confidence interval: 1.1, 4.3) for women with eight or more pregnancies. Miscarriage, particularly as an outcome of the first pregnancy, was also indicated as a risk factor. The association between voluntary abortion and thyroid microcarcinoma could be explained by enhanced medical surveillance and improved cancer detection in women undergoing abortion. Oral contraceptives and hormone replacement therapy were unrelated to thyroid cancer. The very high birth rate among Melanesian women in New Caledonia, as well as late age at menarche, may explain, in part, their elevated incidence of thyroid cancer. [ABSTRACT FROM AUTHOR]

Background Aetiology of differentiated thyroid cancer is poorly understood. Among the risk factors strongly suspected to be involved in thyroid carcinogenesis are dietary factors. Recent evidence suggests polyphenols (i.e. natural bioactive compounds found in plant species), and their anticancer properties, may deserve closer epidemiological attention. Therefore, we examined the association between polyphenol intake levels and thyroid cancer risk in New Caledonia – a Pacific archipelago with some of the highest recorded thyroid cancer incidence rates in the world. Methods Food frequency questionnaire information from a population-based case-control study was used. Daily lignan and flavonoid intakes, expressed as aglycone equivalents, were estimated using Phenol-Explorer and relevant USDA databases. Unconditional logistic regression analyses were performed on data from 324 histologically confirmed cases of papillary or follicular carcinoma, diagnosed from 1993 to 1999, and 402 controls. Polyphenol intakes were analysed as both continuous and categorical variables (quartiles). Results Estimated median flavonoid and lignan intakes were 351.0 and 2.6 mg, respectively. When adjusting for sex, age, ethnic community, province of residence, BMI, smoking status, alcohol consumption and energy intake, no association with differentiated thyroid cancer risk was observed for flavonoids (OR = 1.06, 95% CI: 0.66, 1.70; comparing extreme quartiles), but a negative association was demonstrated for lignans (ORQ4vs.Q1=0.60, 95% CI: 0.37, 0.96; comparing extreme quartiles). Conclusions Our findings suggest that lignans may exert a protective effect on differentiated thyroid cancer. However, large-scale cohort studies and further analytical data on lignans are required to confirm this association. Key messages Lignans may play a role in thyroid carcinogenesis. [ABSTRACT FROM AUTHOR]

Background:There is extensive epidemiological evidence that menopausal hormone therapy (MHT) increases breast cancer risk, particularly combinations of estrogen and progestagen (EP). We investigated the effects of the specific formulations and types of therapies used by French women. Progestagen constituents, regimen (continuous or sequential treatment by the progestagen), and time interval between onset of menopause and start of MHT were examined. Methods:We conducted a population-based case-control study in France in 1555 menopausal women (739 cases and 816 controls). Detailed information on MHT use was obtained during in-person interviews. Odds ratios and 95% confidence interval adjusted for breast cancer risk factors were calculated. Results:We found that breast cancer risk differed by type of progestagen among current users of EP therapies. No increased risk was apparent among EP therapy users treated with natural micronized progesterone. Among users of EP therapy containing a synthetic progestin, the odds ratio was 1.57 (0.99-2.49) for progesterone-derived and 3.35 (1.07-10.4) for testosterone-derived progestagen. Women with continuous regimen were at greater risk than women treated sequentially, but regimen and type of progestagen could not be investigated independently, as almost all EP combinations containing a testosterone-derivative were administered continuously and vice-versa. Tibolone was also associated with an increased risk of breast cancer. Early users of MHT after onset of menopause were at greater risk than users who delayed treatment. Conclusion:This study confirms differential effects on breast cancer risk of progestagens and regimens specifically used in France. Formulation of EP therapies containing natural progesterone, frequently prescribed in France, was not associated with increased risk of breast cancer but may poorly protect against endometrial cancer. [ABSTRACT FROM AUTHOR]