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Background The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results. Methods Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. Results During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10–11 years; HR, 1.28; 95% CI, 1.00–1.64), younger (<40; HR, 1.31; 95% CI, 1.05–1.62) and older (≥55; HR, 1.33; 95% CI, 1.05–1.68) ages at menopause (vs 40–44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02–1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13–1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00–1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76–0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70–0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles. Conclusions Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight. [ABSTRACT FROM AUTHOR]

Background: Mammogram risk scores based on texture and density defined by different brightness thresholds are associated with breast cancer risk differently and could reveal distinct information about breast cancer risk. We aimed to investigate causal relationships between these intercorrelated mammogram risk scores to determine their relevance to breast cancer aetiology. Methods: We used digitised mammograms for 371 monozygotic twin pairs, aged 40–70 years without a prior diagnosis of breast cancer at the time of mammography, from the Australian Mammographic Density Twins and Sisters Study. We generated normalised, age-adjusted, and standardised risk scores based on textures using the Cirrus algorithm and on three spatially independent dense areas defined by increasing brightness threshold: light areas, bright areas, and brightest areas. Causal inference was made using the Inference about Causation from Examination of FAmilial CONfounding (ICE FALCON) method. Results: The mammogram risk scores were correlated within twin pairs and with each other (r = 0.22–0.81; all P < 0.005). We estimated that 28–92% of the associations between the risk scores could be attributed to causal relationships between the scores, with the rest attributed to familial confounders shared by the scores. There was consistent evidence for positive causal effects: of Cirrus, light areas, and bright areas on the brightest areas (accounting for 34%, 55%, and 85% of the associations, respectively); and of light areas and bright areas on Cirrus (accounting for 37% and 28%, respectively). Conclusions: In a mammogram, the lighter (less dense) areas have a causal effect on the brightest (highly dense) areas, including through a causal pathway via textural features. These causal relationships help us gain insight into the relative aetiological importance of different mammographic features in breast cancer. For example our findings are consistent with the brightest areas being more aetiologically important than lighter areas for screen-detected breast cancer; conversely, light areas being more aetiologically important for interval breast cancer. Additionally, specific textural features capture aetiologically independent breast cancer risk information from dense areas. These findings highlight the utility of ICE FALCON and family data in decomposing the associations between intercorrelated disease biomarkers into distinct biological pathways. [ABSTRACT FROM AUTHOR]

Background The extent to which known and unknown factors explain how much people of the same age differ in disease risk is fundamental to epidemiology. Risk factors can be correlated in relatives, so familial aspects of risk (genetic and non-genetic) must be considered. Development We present a unifying model (VALID) for variance in risk, with risk defined as log(incidence) or logit(cumulative incidence). Consider a normally distributed risk score with incidence increasing exponentially as the risk increases. VALID's building block is variance in risk, Δ2, where Δ = log(OPERA) is the difference in mean between cases and controls and OPERA is the odds ratio per standard deviation. A risk score correlated r between a pair of relatives generates a familial odds ratio of exp(r Δ2). Familial risk ratios, therefore, can be converted into variance components of risk, extending Fisher's classic decomposition of familial variation to binary traits. Under VALID, there is a natural upper limit to variance in risk caused by genetic factors, determined by the familial odds ratio for genetically identical twin pairs, but not to variation caused by non-genetic factors. Application For female breast cancer, VALID quantified how much variance in risk is explained—at different ages—by known and unknown major genes and polygenes, non-genomic risk factors correlated in relatives, and known individual-specific factors. Conclusion VALID has shown that, while substantial genetic risk factors have been discovered, much is unknown about genetic and familial aspects of breast cancer risk especially for young women, and little is known about individual-specific variance in risk. [ABSTRACT FROM AUTHOR]

Background: Cereal‐derived polyphenols have demonstrated protective mechanisms in colorectal cancer (CRC) models; however, confirmation in human studies is lacking. Therefore, this study examined the association between cereal polyphenol intakes and CRC risk in the Melbourne Collaborative Cohort Study (MCCS), a prospective cohort study in Melbourne, Australia that recruited participants between 1990 and 1994 to investigate diet–disease relationships. Methods: Using food frequency questionnaire diet data matched to polyphenol data, dietary intakes of alkylresorcinols, phenolic acids, lignans, and total polyphenols from cereals were estimated. Hazard ratios (HRs) and 95% confidence intervals for CRC risk were estimated for quintiles of intake with the lowest quintile as the comparison category, using multivariable adjusted Cox proportional hazards models with age as the time axis adjusted for sex, socio‐economic status, alcohol consumption, fibre intake, country of birth, total energy intake, physical activity and smoking status. Results: From 35,245 eligible adults, mean (SD) age 54.7 (8.6) years, mostly female (61%) and Australian‐born (69%), there were 1394 incident cases of CRC (946 colon cancers and 448 rectal cancers). Results for total cereal polyphenol intake showed reduced HRs in Q2 (HR: 0.80; 95% CI, 0.68–0.95) and Q4 (HR: 0.75; 95% CI, 0.62–0.90), and similar for phenolic acids. Alkylresorcinol intake showed reduced HR in Q3 (HR: 0.80; 95% CI, 0.67–0.95) and Q4 (HR: 0.79; 95% CI, 0.66–0.95). Conclusions: Overall, the present study showed little evidence of association between intakes of cereal polyphenols and CRC risk. Future investigations may be useful to understand associations between cereal‐derived polyphenols and additional cancers in different populations. [ABSTRACT FROM AUTHOR]

DNA methylation marks that are inherited from parents to offspring are known to play a role in cancer risk and could explain part of the familial risk for cancer. We therefore conducted a genome-wide search for heritable methylation marks associated with prostate cancer risk. Peripheral blood DNA methylation was measured for 133 of the 469 members of 25 multiple-case prostate cancer families, using the EPIC array. We used these families to systematically search the genome for methylation marks with Mendelian patterns of inheritance, then we tested the 1,000 most heritable marks for association with prostate cancer risk. After correcting for multiple testing, 41 heritable methylation marks were associated with prostate cancer risk. Separate analyses, based on 869 incident cases and 869 controls from a prospective cohort study, showed that 9 of these marks near the metastable epiallele VTRNA2-1 were also nominally associated with aggressive prostate cancer risk in the population. [ABSTRACT FROM AUTHOR]

The kynurenine pathway is increasingly recognised to play a role in inflammation and disease. We assessed the cross-sectional and longitudinal associations of adiposity measures (body mass index, waist-hip ratio, waist circumference and fat mass ratio) with plasma concentrations of kynurenine pathway metabolites and traditional markers of inflammation. We used data from 970 Melbourne Collaborative Cohort Study participants who had plasma markers measured at baseline (median age 59 years) and follow-up (median age 70 years). Linear regression was used to assess cross-sectional and longitudinal associations between four adiposity measures and concentrations of i) nine kynurenine pathway metabolites; ii) two derived markers; iii) eight traditional inflammatory markers. Cross-sectionally, most kynurenine metabolites were strongly associated with adiposity measures at both time points; associations were generally stronger than for most inflammation markers except CRP (e.g. body mass index at baseline, quinolinic acid (per S.D. β = 0.30, 95%CI: 0.24–0.36, P = 10−21), kynurenine (β = 0.25, 95%CI: 0.19–0.31, P = 10−16) and CRP (β = 0.31, 95%CI: 0.25–0.37, P = 10−24), and remained largely unchanged after adjustment for confounders. Longitudinally, changes in adiposity measures over approximately a decade were positively associated with changes in kynurenine metabolite concentrations (in particular for 3-hydroxyanthranilic acid, kynurenine and quinolinic acid), and more strongly so than for other markers of inflammation, including CRP. In middle-aged and older adults, plasma concentrations of kynurenine metabolites are strongly associated with adiposity, both cross-sectionally and longitudinally. Our study demonstrates that kynurenine metabolites may be valuable markers to monitor the adverse consequences of obesity. [ABSTRACT FROM AUTHOR]

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women. [ABSTRACT FROM AUTHOR]

We examined associations between sex‐specific alcohol intake trajectories and alcohol‐related cancer risk using data from 22 756 women and 15 701 men aged 40 to 69 years at baseline in the Melbourne Collaborative Cohort Study. Alcohol intake for 10‐year periods from age 20 until the decade encompassing recruitment, calculated using recalled beverage‐specific frequency and quantity, was used to estimate group‐based sex‐specific intake trajectories. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for primary invasive alcohol‐related cancer (upper aerodigestive tract, breast, liver and colorectum). Three distinct alcohol intake trajectories for women (lifetime abstention, stable light, increasing moderate) and six for men (lifetime abstention, stable light, stable moderate, increasing heavy, early decreasing heavy, late decreasing heavy) were identified. 2303 incident alcohol‐related cancers were diagnosed during 485 525 person‐years in women and 789 during 303 218 person‐years in men. For men, compared with lifetime abstention, heavy intake (mean ≥ 60 g/day) at age 20 to 39 followed by either an early (from age 40 to 49) (early decreasing heavy; HR = 1.75, 95% CI: 1.25‐2.44) or late decrease (from age 60 to 69) (late decreasing heavy; HR = 1.94, 95% CI: 1.28‐2.93), and moderate intake (mean <60 g/day) at age 20 to 39 increasing to heavy intake in middle‐age (increasing heavy; HR = 1.45, 95% CI: 1.06‐1.97) were associated with increased risk of alcohol‐related cancer. For women, compared with lifetime abstention, increasing intake from age 20 (increasing moderate) was associated with increased alcohol‐related cancer risk (HR = 1.25, 95% CI: 1.06‐1.48). Similar associations were observed for colorectal (men) and breast cancer. Heavy drinking during early adulthood might increase cancer risk later in life. [ABSTRACT FROM AUTHOR]

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case–control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS‐based risk prediction, particularly assessment of calibration (comparing predicted to observed risks). Objectives: To evaluate PRS‐based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry. Methods: We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case‐cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single‐nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta‐analysis (PRS68), 50 SNPs significant in the 2020 meta‐analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten‐year melanoma risks were calculated from population‐level cancer registry data by age group and sex, with and without PRS adjustment. Results: Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62–0·68] and MCCS (E/O = 0·63, 95% CI 0·56–0·72). For UKB, calibration was improved by PRS adjustment, with PRS50‐adjusted risks E/O = 0·91, 95% CI 0·87–0·95. The discriminative ability for PRS68‐ and PRS50‐adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07–0·10, P < 0·0001), and higher than for PRS45‐adjusted risks (Δ area under the curve 0·02–0·04, P < 0·001). Conclusions: A PRS derived from a larger, more diverse meta‐analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations. [ABSTRACT FROM AUTHOR]

Purpose: High-grade disease accounts for ~ 70% of all glioma, and has a high mortality rate. Few modifiable exposures are known to be related to glioma risk or mortality. Methods: We examined associations between lifetime physical activity and physical activity at different ages (15–18 years, 19–29 years, 30–39 years, last 10 years) with the risk of glioma diagnosis, using data from a hospital-based family case–control study (495 cases; 371 controls). We followed up cases over a median of 25 months to examine whether physical activity was associated with all-cause mortality. Physical activity and potential confounders were assessed by self-administered questionnaire. We examined associations between physical activity (metabolic equivalent [MET]-h/wk) and glioma risk using unconditional logistic regression and with all-cause mortality in cases using Cox regression. Results: We noted a reduced risk of glioma for the highest (≥ 47 MET-h/wk) versus lowest (< 24 METh/wk) category of physical activity for lifetime activity (OR = 0.58, 95% CI: 0.38–0.89) and at 15–18 years (OR = 0.57, 95% CI: 0.39–0.83). We did not observe any association between physical activity and all-cause mortality (HR for lifetime physical activity = 0.91, 95% CI: 0.64–1.29). Conclusion: Our findings are consistent with previous research that suggested physical activity during adolescence might be protective against glioma. Engaging in physical activity during adolescence has many health benefits; this health behavior may also offer protection against glioma. [ABSTRACT FROM AUTHOR]

Background Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. Objectives The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. Methods We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2) ] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. Results The hepcidin-regulating gene pathway was significantly associated with PDAC (P  = 0.002), with the HJV, TFR2, TFR1, BMP6 , and HAMP genes contributing the most to the association. Conclusions Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association. [ABSTRACT FROM AUTHOR]

Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).Methods and Findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer. [ABSTRACT FROM AUTHOR]

Alcohol consumption is a known cause of cancer, but its role in the etiology of second primary (metachronous) cancer is uncertain. Associations between alcohol intake up until study enrollment (prediagnosis) and risk of metachronous cancer were estimated using 9435 participants in the Melbourne Collaborative Cohort Study who were diagnosed with their first invasive cancer after enrollment (1990‐1994). Follow‐up was from date of first invasive cancer until diagnosis of metachronous cancer, death or censor date (February 2018), whichever came first. Alcohol intake for 10‐year periods from age 20 until decade encompassing baseline using recalled beverage‐specific frequency and quantity was used to calculate baseline and lifetime intakes, and group‐based intake trajectories. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. After a mean follow‐up of 7 years, 1512 metachronous cancers were identified. A 10 g/d increment in prediagnosis lifetime alcohol intake (HR = 1.03, 95% CI = 1.00‐1.06; Pvalue =.02) and an intake of ≥60 g/d (HR = 1.32, 95% CI = 1.01‐1.73) were associated with increased metachronous cancer risk. We observed positive associations (per 10 g/d increment) for metachronous colorectal (HR = 1.07, 95% CI = 1.00‐1.14), upper aero‐digestive tract (UADT) (HR = 1.16, 95% CI = 1.00‐1.34) and kidney cancer (HR = 1.24, 95% CI = 1.10‐1.39). Although these findings were partly explained by effects of smoking, the association for kidney cancer remained unchanged when current smokers or obese individuals were excluded. Alcohol intake trajectories over the life course confirmed associations with metachronous cancer risk. Prediagnosis long‐term alcohol intake, and particularly heavy drinking, may increase the risk of metachronous cancer, particularly of the colorectum, UADT and kidney. What's new Alcohol consumption is an important risk factor for certain cancer types. Whether alcohol also has a role in the development of second primary tumors known as metachronous cancers, however, is uncertain. Here, an investigation of pre‐diagnosis long‐term alcohol intake and metachronous cancer in nearly 10,000 cancer survivors reveals associations between increasing alcohol consumption and metachronous cancers of the colorectum, upper aero‐digestive tract, and kidney. The associations were partly modified by smoking behavior. These findings offer new insights into risk factors for subsequent cancers in cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age.Methods: We used the Prospective Family Cohort Study of 14 657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk models when using the alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were 2-sided.Results: Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff < .001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or older, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA.Conclusions: Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years. [ABSTRACT FROM AUTHOR]

Our study aimed to assess the value of DNA methylation for prediction purposes, whereas the main points raised by Meng relate to the aetiology of lung and bladder cancer using "causal methods". Biological aging measures based on blood DNA methylation and risk of cancer: a prospective study. [Extracted from the article]

Background Higher intakes of whole grains and dietary fiber have been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for cancer. Objectives Because the evidence of association with bladder cancer (BC) is limited, we aimed to assess associations with BC risk for intakes of whole grains, refined grains, and dietary fiber. Methods We pooled individual data from 574,726 participants in 13 cohort studies, 3214 of whom developed incident BC. HRs, with corresponding 95% CIs, were estimated using Cox regression models stratified on cohort. Dose–response relations were examined using fractional polynomial regression models. Results We found that higher intake of total whole grain was associated with lower risk of BC (comparing highest with lowest intake tertile: HR: 0.87; 95% CI: 0.77, 0.98; HR per 1-SD increment: 0.95; 95% CI: 0.91, 0.99; P for trend: 0.023). No association was observed for intake of total refined grain. Intake of total dietary fiber was also inversely associated with BC risk (comparing highest with lowest intake tertile: HR: 0.86; 95% CI: 0.76, 0.98; HR per 1-SD increment: 0.91; 95% CI: 0.82, 0.98; P for trend: 0.021). In addition, dose–response analyses gave estimated HRs of 0.97 (95% CI: 0.95, 0.99) for intake of total whole grain and 0.96 (95% CI: 0.94, 0.98) for intake of total dietary fiber per 5-g daily increment. When considered jointly, highest intake of whole grains with the highest intake of dietary fiber showed 28% reduced risk (95% CI: 0.54, 0.93; P for trend: 0.031) of BC compared with the lowest intakes, suggesting potential synergism. Conclusions Higher intakes of total whole grain and total dietary fiber are associated with reduced risk of BC individually and jointly. Further studies are needed to clarify the underlying mechanisms for these findings. [ABSTRACT FROM AUTHOR]

Rationale: Interactions between early life and adult insults on lung function decline are not well understood, with most studies investigating prebronchodilator (pre-BD) FEV1 decline.Objectives: To investigate relationships between adult risk factors and pre- and post-BD lung function decline and their potential effect modification by early life and genetic factors.Methods: Multiple regression was used to examine associations between adult exposures (asthma, smoking, occupational exposures, traffic pollution, and obesity) and decline in both pre- and post-BD spirometry (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC], and FEV1/FVC) between ages 45 and 53 years in the Tasmanian Longitudinal Health Study (n = 857). Effect modification of these relationships by childhood respiratory risk factors, including low childhood lung function and GST (glutathione S-transferase) gene polymorphisms, was investigated.Results: Baseline asthma, smoking, occupational exposure to vapors/gases/dusts/fumes, and living close to traffic were associated with accelerated decline in both pre- and post-BD FEV1. These factors were also associated with FEV1/FVC decline. Occupational exposure to aromatic solvents was associated with pre-BD but not post-BD FEV1 decline. Maternal smoking accentuated the effect of personal smoking on pre- and post-BD FEV1 decline. Lower childhood lung function and having the GSTM1 null allele accentuated the effect of occupational exposure to vapors/gases/dusts/fumes and personal smoking on post-BD FEV1 decline. Incident obesity was associated with accelerated decline in FEV1 and more pronounced in FVC.Conclusions: This study provides new evidence for accentuation of individual susceptibility to adult risk factors by low childhood lung function, GSTM1 genotype, and maternal smoking. [ABSTRACT FROM AUTHOR]

Purpose: The role of diet in bladder carcinogenesis has yet to be established. To date most studies have investigated dietary components individually, rather than as dietary patterns, which may provide stronger evidence for any influence of diet on bladder carcinogenesis. The Mediterranean diet has been associated with many health benefits, but few studies have investigated its association with bladder cancer risk. Methods: We investigated the potential association between the Mediterranean diet score (MDS) and risk of developing bladder cancer by pooling 13 prospective cohort studies included in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study and applying a Cox regression analysis. Results: Dietary data from 646,222 study participants, including 3639 incident bladder cancer cases, were analysed. We observed an inverse association between Mediterranean diet and bladder cancer risk (HRhigh 0.85 [95% CI 0.77, 0.93]). When stratifying the results on non-muscle-invasive or muscle-invasive disease or sex the association remained similar and the HR estimate was consistently below 1.00 both for medium and high adherence to the Mediterranean diet. A consistent association was observed when disregarding fat or alcohol intake. Conclusion: We found evidence that adherence to the Mediterranean diet was associated with reduced risk of developing bladder cancer, suggesting a positive effect of the diet as a whole and not just one component. [ABSTRACT FROM AUTHOR]

Background: Adherence to a traditional Mediterranean diet has been associated with lower mortality and cardiovascular disease risk. The relative importance of diet compared to other lifestyle factors and effects of dietary patterns over time remains unknown.Methods: We used the parametric G-formula to account for time-dependent confounding, in order to assess the relative importance of diet compared to other lifestyle factors and effects of dietary patterns over time. We included healthy Melbourne Collaborative Cohort Study participants attending a visit during 1995-1999. Questionnaires assessed diet and physical activity at each of three study waves. Deaths were identified by linkage to national registries. We estimated mortality risk over approximately 14 years (1995-2011).Results: Of 22,213 participants, 2163 (9.7%) died during 13.6 years median follow-up. Sustained high physical activity and adherence to a Mediterranean-style diet resulted in an estimated reduction in all-cause mortality of 1.82 per 100 people (95% confidence interval (CI): 0.03, 3.6). The population attributable fraction was 13% (95% CI: 4, 23%) for sustained high physical activity, 7% (95% CI: - 3, 17%) for sustained adherence to a Mediterranean-style diet and 18% (95% CI: 0, 36%) for their combination.Conclusions: A small reduction in mortality may be achieved by sustained elevated physical activity levels in healthy middle-aged adults, but there may be comparatively little gain from increasing adherence to a Mediterranean-style diet. [ABSTRACT FROM AUTHOR]

Purpose: Diet and body size may affect the risk of aggressive prostate cancer (APC), but current evidence is inconclusive.Methods: A case-control study was conducted in men under 75 years of age recruited from urology practices in Victoria, Australia; 1,254 with APC and 818 controls for whom the presence of prostate cancer had been excluded by biopsy. Dietary intakes were assessed using a validated food frequency questionnaire. Multivariable unconditional logistic regression estimated odds ratios and confidence intervals for hypothesized risk factors, adjusting for age, family history of prostate cancer, country of birth, socioeconomic status, smoking, and other dietary factors.Results: Positive associations with APC (odds ratio, 95% confidence intervals, highest vs. lowest category or quintile) were observed for body mass index (1.34, 1.02-1.78, Ptrend = 0.04), and trouser size (1.54, 1.17-2.04, Ptrend = 0.001). Intakes of milk and all dairy products were inversely associated with APC risk (0.71, 9.53-0.96, Ptrend = 0.05, and 0.64, 0.48-0.87, Ptrend = 0.012, respectively), but there was little evidence of an association with other dietary variables (Ptrend > 0.05).Conclusions: We confirmed previous evidence for a positive association between body size and risk of APC, and suggest that consumption of dairy products, and milk more specifically, is inversely associated with risk. [ABSTRACT FROM AUTHOR]

Objective: To examine the associations of female reproductive and hormonal factors with incidence of total knee arthroplasty (TKA) for osteoarthritis (OA), and to determine whether the associations differ according to overweight/obesity status. Methods: This study included 22,289 women in the Melbourne Collaborative Cohort Study. Data on age at menarche, pregnancy, parity, years of menstruation, oral contraceptive (OC) use, menopausal status, and hormone replacement therapy (HRT) were collected in 1990–1994. Incidence of TKA during 2001–2013 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. All analyses were adjusted for age, body mass index (BMI) at midlife, change in BMI (from early reproductive age to midlife), country of birth, physical activity, smoking, and education level. Results: Over the course of 12.7 years, 1,208 TKAs for OA were identified. Ever being pregnant was associated with increased risk of TKA (hazard ratio [HR] 1.32 [95% confidence interval (95% CI) 1.06–1.63]). Parity was positively associated with risk of TKA (P for trend = 0.003). OC users had increased risk of TKA compared with non‐users (for OC use of <5 years, HR 1.25 [95% CI 1.08–1.45]; for OC use of ≥5 years, HR 1.17 [95% CI 1.00–1.37]). A 1‐year increase in menstruation was associated with a 1% decrease in risk of TKA (HR 0.99 [95% CI 0.97–0.99]). These associations remained significant only in women of normal weight at early reproductive age. Current HRT users had increased risk of TKA compared with non‐users (HR 1.37 [95% CI 1.14–1.64]); the association was significant only in non‐obese women at midlife. Conclusion: Reproductive and hormonal factors were associated with risk of knee OA. These associations remained significant in women of normal weight at early reproductive age and in non‐obese women at midlife. Further work is needed to understand the complex effect of these factors on knee OA. [ABSTRACT FROM AUTHOR]

Age-related loss of skeletal muscle is associated with increased risk of functional limitation and cardiovascular (CV) mortality. In the elderly abdominal aortic calcification (AAC) can increase CV risk by altering aortic properties which may raise blood pressure and increase cardiac workload. This study investigated the association between low muscle mass and AAC in community-dwelling older Australians. Data for this cross-sectional analysis were drawn from a 2010 sub-study of the Melbourne Collaborative Cohort Study in the setting of community-dwelling older adults. Three hundred and twenty-seven participants [mean age = 71 ± 6 years; mean BMI = 28 ± 5 kg/m(2); females n = 199 (62 %)] had body composition determined by dual-energy x-ray absorptiometry (DXA) and AAC determined by radiography. Participants were stratified into tertiles of sex-specific BMI-normalised appendicular lean mass (ALM). Those in the lowest tertile were considered to have low relative muscle mass. Aortic calcification score (ACS) was determined visually as the extent of calcification on the aortic walls between L1 and L4 vertebrae (range: 0-24). Severe AAC was defined as ACS ≥ 6. Prevalence of any AAC was highest in participants with low relative muscle mass (74 %) compared to the middle (65 %) and upper (53 %) tertiles (p trend = 0.006). The lower ALM/BMI tertile had increased odds (Odds ratio = 2.3; 95 % confidence interval: 1.1-4.6; p = 0.021) of having any AAC; and having more severe AAC (2.2; 1.2-4.0; p = 0.009) independent of CV risk factors, serum calcium and physical activity. AAC is more prevalent and severe in community-dwelling older adults with low relative muscle mass. Maintaining muscle mass could form part of a broader primary prevention strategy in reducing AAC. [ABSTRACT FROM AUTHOR]

Little evidence exists regarding associations between age-related macular degeneration (AMD) and moderate alcohol consumption, patterns of consumption, or different types of alcoholic beverage. The authors examined associations between AMD prevalence and alcohol intake using 20,963 participants from the Melbourne Collaborative Cohort Study aged 40–69 years at baseline (1990–1994). Participants' alcohol consumption was determined from a structured interview at baseline. At follow-up from 2003 to 2007, digital macula photographs of both eyes were taken and evaluated for early and late AMD signs. Drinking more than 20 g of alcohol per day was associated with an approximate 20% increase in the odds of early AMD (odds ratio = 1.21, 95% confidence interval: 1.06, 1.38; P = 0.004) when compared with those who reported no alcohol intake at baseline, having adjusted for sex, age, smoking, country of birth, education, physical activity, and energy from food. This positive association was apparent for wine, beer, and spirits. The estimates were similar for both sexes. The odds ratio for those drinking more than 20 g of alcohol per day for late AMD was 1.44 (95% confidence interval: 0.85, 2.45; P = 0.17). These results show a modest association between alcohol consumption and increased AMD risk. [ABSTRACT FROM PUBLISHER]

Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease.Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case–control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants.Results Among men, we found a positive association between height and glioma risk (&geq;190 vs 170–174 cm, pooled OR = 1.70, 95% CI: 1.11–2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17–3.38; P-trend = 0.02). Among women, these associations were less clear (&geq;175 vs 160–164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70–1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77–2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk.Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease. [ABSTRACT FROM PUBLISHER]

Evidence for an association between age-related macular degeneration (AMD) and obesity is inconsistent. The authors examined associations between adiposity and AMD prevalence using 21,287 participants from the Melbourne Collaborative Cohort Study aged 40–69 years at baseline (1990–1994). For men, each increase of 0.1 in waist/hip ratio (∼1 standard deviation) was associated with a 13% increase in the odds of early AMD (odds ratio = 1.13, 95% confidence interval: 1.01, 1.26; P = 0.03) and a 75% increase in the odds of late AMD (odds ratio = 1.75, 95% confidence interval: 1.11, 2.76; P = 0.02). No other adiposity measure was associated with early AMD for men. Smoking status modified the relation between waist/hip ratio and early AMD (P = 0.05), with no association for former smokers. For women, there were inverse associations with early AMD for all adiposity measures (odds ratios = 0.89–0.93; P = 0.002–0.02), but no associations were observed for late AMD. This study confirms abdominal obesity as an AMD risk factor for men despite a survivorship effect from competing risks in morbidity and mortality. The inverse associations for women may reflect weaker true positive associations with AMD that are insufficient to overcome the survivorship effect. New data are provided on complex interactions between environmental exposures and AMD risk. [ABSTRACT FROM PUBLISHER]

The article discusses a study which investigated the association between alcohol consumption and risk of glioblastoma, using data from the Melbourne Collaborative Cohort Study in Victoria. Cox regression models were used to estimate hazard ratios (HR). The study found that baseline alcohol consumption was associated with glioblastoma risk in a dose-response relationship.

Discovering and understanding genetic risk factors for melanoma and their interactions with phenotype, sun exposure, and other risk factors could lead to new strategies for melanoma control. This paper describes the Australian Melanoma Family Study, which uses a multicenter, population-based, case-control-family design. From 2001 to 2005, the authors recruited 1,164 probands including 629 cases with histopathologically confirmed, first-primary cutaneous melanoma diagnosed before age 40 years, 240 population-based controls frequency matched for age, and 295 spouse/friend controls. Information on lifetime sun exposure, phenotype, and residence history was collected for probands and nearly 4,000 living relatives. More than 3,000 subjects donated a blood sample. Proxy-reported information was collected for childhood sun exposure and deceased relatives. Important features of this study include the population-based, family-based design; a focus on early onset disease; probands from 3 major cities differing substantially in solar ultraviolet exposure and melanoma incidence; a population at high risk because of high ultraviolet exposure and susceptible pigmentation phenotypes; population-based, spouse/friend, and sibling controls; systematic recruitment of relatives of case and control probands; self and parent reports of childhood sun exposure; and objective clinical skin examinations. The authors discuss methodological and analytical issues related to the study design and conduct, as well as the potentially novel insights the study can deliver. [ABSTRACT FROM PUBLISHER]

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10−5). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10−5). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity. [ABSTRACT FROM AUTHOR]

The article discusses a study which aimed to determine whether anthropometric and body composition measures, assessed over 10 years, were related to articular patella cartilage volume and defects in healthy adults with no clinical knee osteoarthritis (OA). Findings suggest that interventions targeting a reduction in adipose tissue may help reduce the risk for the onset and progression of patellofemoral OA, particularly in women.

Objective To evaluate the effect of dietary folate intake on the relation between alcohol consumption and breast cancer risk. Design Prospective cohort study. Setting Melbourne, Australia. Participants 17 447 Anglo-Australian women resident in Melbourne, aged 40-69 years at recruitment in 1990-4, and followed up until 31 December 2003. Main outcome measure Invasive breast cancers diagnosed during follow-up and ascertained through the Victorian cancer registry. Results 537 invasive breast cancers were diagnosed. Compared with lifetime abstainers, the hazard ratio for breast cancer in women who consumed an average of 40 g or more of alcohol daily at baseline was 1.41 (95% confidence interval 0.90 to 2.23). No direct association was found between dietary folate intake and risk of breast cancer, but a high folate intake mitigated the excess risk associated with alcohol. The estimated hazard ratio of an alcohol consumption of 40 g/day or more was 2.00 (1.14 to 3.49) for women with intakes of 200 µg/day of folate and 0.77 (0.33 to 1.80) for 400 µg/day of folate (P = 0.04 for interaction between alcohol and folate). Conclusions An adequate dietary intake of folate might protect against the increased risk of breast cancer associated with alcohol consumption. [ABSTRACT FROM AUTHOR]

Much research has investigated possible links between diet and the risk of colorectal cancer, but little is known about whether dietary habits influence prognosis following diagnosis. Incident cases of colorectal cancer were ascertained among participants of the Melbourne Collaborative Cohort Study, a prospective cohort study of 41 528 Australians recruited between 1990 and 1994. Eligible participants had to be diagnosed with a first colorectal cancer between recruitment and 1 August 2002. At recruitment, participants answered a detailed food frequency questionnaire regarding their usual diet. Information on tumor site and stage, treatments given, recurrences and deaths was obtained from a systematic review of medical records. Altogether, 526 cases of colorectal cancer were ascertained in the follow-up period. Median follow up time among survivors was 5.5 years and 208 deaths had occurred, including 181 from colorectal cancer. The usual diet measured before diagnosis was not associated with either all-cause, or colorectal cancer-specific, mortality. No association was observed for diets high in meat, fruit, vegetables or fiber. Our study shows no association between usual diet measured sometime before diagnosis and survival from colorectal cancer. [ABSTRACT FROM AUTHOR]

The Victorian Family Heart Study was established to address the causes of familial patterns in cardiovascular risk factors. From 1990 to 1996, a representative population sample of 783 adult families (2,959 individuals), each comprising both parents (40–70 years) and at least one natural adult offspring (18–30 years), was recruited in Melbourne, Australia. Included in both generations were 461 monozygotic and dizygotic twins as pairs or singletons. A multivariate normal model was used for pedigree analysis of height, weight, body mass index, diastolic and systolic blood pressure, pulse rate, and total and high density lipoprotein cholesterol. All traits showed evidence for additive genetic variation, explaining from 55% (height) to 26% (pulse) of age- and sex-adjusted variance. An effect persisting into adulthood of shared family environment during cohabitation explained from 39% (body mass index) to 13% (systolic blood pressure) of variance (not nominally significant for diastolic blood pressure). These shared environmental effects were strongest within twin pairs, less so for sibling pairs, and least for parent-offspring pairs (in which an effect was not observed for weight, diastolic and systolic blood pressure, and total cholesterol). On a background of genetic influences, there are periods in early life during which the family environment cements long-term correlations between adult relatives in cardiovascular risk factors. Am J Epidemiol 2000;152:704–15. [ABSTRACT FROM PUBLISHER]

Background Greater physical activity (PA) and less sitting time (ST) have been associated with lower breast cancer (BC) risk in observational studies, but causality is undetermined. Mendelian randomization (MR) investigates causality by using genotype to simulate randomized trials within observational data. A recent summary-data MR study assessed PA and BC by estrogen-receptor (ER) status. We aimed to examine PA and ST in relation to invasive BC risk overall and by molecular subtype. Methods We performed two-sample MR using individual-level Breast Cancer Association Consortium data from 125,684 women (69,869 cases), and summary-level UK Biobank genetic data for the exposure (n = 91,105). We used imputed single nucleotide polymorphisms (SNPs) previously associated (p < 5x10-8) with accelerometer-measured PA (n-SNPs=5) or ST (n = 6). We estimated odds ratios (OR) from inverse-variance weighted MR. Results Greater PA was associated with lower risk of BC (OR = 0.48;95%CI=0.30-0.78 per standard deviation [SD] in activity). Estimates were inverse for all subtypes, particularly ER + (OR=0.45; 95%CI=0.25-0.83), PR + (OR=0.43;95%CI=0.22-0.85), and HER2 + (OR = 0.48; 95%CI=0.26-0.89). Greater ST was associated with higher risk of hormone-receptor-negative tumours, particularly triple-negative (ER-/PR-/HER2-) (OR = 2.04; 95%CI=1.06-3.93 per SD in ST). Estimates overall and for most other subtypes were elevated but had wide CIs crossing null. Sensitivity analyses (weighted-median MR and MR-Egger) did not suggest strong pleiotropic effects for either exposure. Conclusions Greater PA and lower ST reduces risk of all breast cancers, and hormone-receptor negative tumours, respectively. More widespread adoption of active lifestyles will lower burden from the most common cancer in women. Key messages More active and less sedentary lifestyles reduce risk of breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Ageing is the strongest cancer risk factor, and men and women exhibit different risk profiles in terms of incidence and survival. DNA methylation is known to strongly vary by age and sex. Epigenetic drift refers to age-related DNA methylation changes and the tendency for increasing discordance between epigenomes over time, but it remains unknown to what extent the epigenetic drift contributes to cancer risk and survival. The aims of this study were to identify age-associated, sex-associated and sexually dimorphic age-associated (age-by-sex-associated) DNA methylation markers and investigate whether age- and age-by-sex-associated markers are associated with cancer risk and survival. Our study, which used a total of 2754 matched case–control pairs with DNA methylation in pre-diagnostic blood, is the first large study to examine the association between sex-specific epigenetic drift and cancer development and progression. The results may be useful for cancer early diagnosis and prediction of prognosis. To investigate age- and sex-specific DNA methylation alterations related to cancer risk and survival, we used matched case–control studies of colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869) and urothelial (n = 428) cancers, and mature B-cell lymphoma (n = 438). Linear mixed-effects models were conducted to identify age-, sex- and age-by-sex-associated methylation markers using a discovery (controls)-replication (cases) strategy. Replication was further examined using summary statistics from Generation Scotland (GS). Associations between replicated markers and risk of and survival from cancer were assessed using conditional logistic regression and Cox models (hazard ratios (HR)), respectively. We found 32,659, 23,141 and 48 CpGs with replicated associations for age, sex and age-by-sex, respectively. The replication rates for these CpGs using GS summary data were 94%, 86% and 91%, respectively. Significant associations for cancer risk and survival were identified at some individual age-related CpGs. Opposite to previous findings using epigenetic clocks, there was a strong negative trend in the association between epigenetic drift and risk of colorectal cancer. Methylation at two CpGs overlapping TMEM49 and ARX genes was associated with survival of overall (HR = 0.91, p = 7.7 × 10−4) and colorectal (HR = 1.52, p = 1.8 × 10−4) cancer, respectively, with significant age-by-sex interaction. Our results may provide markers for cancer early detection and prognosis prediction. [ABSTRACT FROM AUTHOR]

Simple Summary: Identifying which men at the time of prostate cancer diagnosis have, or will progress to, an aggressive fatal disease will allow clinicians to assist men in making better informed treatment decisions. This will not only be important for those men whose disease is likely to remain indolent and who are currently undergoing unnecessary treatment procedures, but also for those who may need to be targeted with immediate and potentially life-saving therapy. Our case-control study confirms that men who carry BRCA1, BRCA2 and ATM germline pathogenic variants are at increased risk of aggressive disease and provides risk estimates that will be used by clinicians to improve counselling. While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7–12.4)), BRCA1 (5.5 (1.8–16.6)), and ATM (3.8 (1.6–9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment. [ABSTRACT FROM AUTHOR]

Our study identified multiple novel loci associated with bladder cancer susceptibility, bringing the number of independent markers at genome-wide significance to 24. Genetic susceptibility markers, coupled with lifestyle risk factors such as smoking, could guide future preventive measures and screening strategies for bladder cancer. Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. Data from 32 studies that includes 13,790 bladder cancer cases and 343, 502 controls of European ancestry were used for meta-analysis. Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10−8) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2 ; multiplicative p value for interaction [ p M-I ] = 0.004), 8q21.13 (PAG1 ; p M-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A ; p M-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44–1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers. We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer. We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer. [ABSTRACT FROM AUTHOR]

Introduction: We hypothesised that breast cancer risk for relatives of women with early-onset breast cancer could be predicted by tumour morphological features.Methods: We studied female first-degree relatives of a population-based sample of 452 index cases with a first primary invasive breast cancer diagnosed before the age of 40 years. For the index cases, a standardised tumour morphology review had been conducted for all; estrogen (ER) and progesterone receptor (PR) status was available for 401 (89%), and 77 (17%) had a high-risk mutation in a breast cancer susceptibility gene or methylation of the BRCA1 promoter region in peripheral blood DNA. We calculated standardised incidence ratios (SIR) by comparing the number of mothers and sisters with breast cancer with the number expected based on Australian incidence rates specific for age and year of birth.Results: Using Cox proportional hazards modelling, absence of extensive sclerosis, extensive intraductal carcinoma, absence of acinar and glandular growth patterns, and the presence of trabecular and lobular growth patterns were independent predictors with between a 1.8- and 3.1-fold increased risk for relatives (all P <0.02). Excluding index cases with known genetic predisposition or BRCA1 promoter methylation, absence of extensive sclerosis, circumscribed growth, extensive intraductal carcinoma and lobular growth pattern were independent predictors with between a 2.0- and 3.3-fold increased risk for relatives (all P <0.02). Relatives of the 128 (34%) index cases with none of these four features were at population risk (SIR = 1.03, 95% CI = 0.57 to 1.85) while relatives of the 37 (10%) index cases with two or more features were at high risk (SIR = 5.18, 95% CI = 3.22 to 8.33).Conclusions: This wide variation in risks for relatives based on tumour characteristics could be of clinical value, help discover new breast cancer susceptibility genes and be an advance on the current clinical practice of using ER and PR as pathology-based predictors of familial and possibly genetic risks. [ABSTRACT FROM AUTHOR]

Background While the relationship between socio-economic disadvantage and cardiovascular disease (CVD) is well established, the role that traditional cardiovascular risk factors play in this association remains unclear. The authors examined the association between education attainment and CVD mortality and the extent to which behavioural, social and physiological factors explained this relationship. Methods Adults (n=38⇔355) aged 40-69 years living in Melbourne, Australia were recruited in 1990-1994. Subjects with baseline CVD risk factor data ascertained through questionnaire and physical measurement were followed for an average of 9.4 years with CVD deaths verified by review of medical records and autopsy reports. Results CVD mortality was higher for those with primary education only, compared with those who had completed tertiary education, with an HR of 1.66 (95% CI 1.10 to 2.49) after adjustment for age, country of birth and gender. Those from the lowest educated group had a more adverse cardiovascular risk factor profile compared with the highest educated group, and adjustment for these risk factors reduced the HR to 1.18 (95% CI 0.78 to 1.77). In analysis of individual risk factors, smoking and waist circumference explained most of the difference in CVD mortality between the highest and lowest education groups. Conclusions Most of the excess CVD mortality in lower socio-economic groups can be explained by known risk factors, particularly smoking and overweight. While targeting cardiovascular risk factors should not divert efforts from addressing the underlying determinants of health inequalities, it is essential that known risk factors are addressed effectively among lower socio-economic groups. [ABSTRACT FROM AUTHOR]

The association between obesity and multiple myeloma (MM) risk may be partly attributed to reduced circulating levels of adiponectin in obese individuals. To prospectively evaluate MM risk in relation to adiponectin levels overall and stratified by body mass index and other characteristics, we conducted a pooled investigation of pre-diagnosed peripheral blood samples from 624 MM cases and 1,246 individually matched controls from seven cohorts participating in the MM Cohort Consortium. Analysis of circulating analyte levels measured by enzyme-linked immunosorbent assays revealed that higher total adiponectin levels were associated with reduced MM risk overall (highest quartile vs. lowest: odds ratio [OR]=0.64, 95% confidence interval [CI]=0.47-0.85; Ptrend = 0.001). This association was apparent among cases diagnosed six or more years after blood collection (OR=0.60, CI=0.40-0.90; Ptrend = 0.004) and was similar in magnitude for men and women (OR=0.59 and 0.66, respectively). Interestingly, we observed strong associations among subjects who were overweight (OR=0.41, CI=0.26-0.65) or obese (OR=0.41, CI=0.17-0.98) but not among those with normal weight (OR=1.20, CI=0.73-2.00; overweight/obese vs. normal weight, Pinteraction = 0.04). Our findings provide the strongest epidemiologic evidence to date that adiponectin protects against MM development, particularly among overweight and obese individuals, and offer a method for risk assessment in this susceptible population of heavier patients. [ABSTRACT FROM AUTHOR]