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Despite overall improvements in cancer survival due to earlier diagnosis and better treatment, socio-economically disadvantaged people have lower cancer survival than more advantaged people. We aimed to examine differences in cancer survival by area-level socio-economic disadvantage in Victoria, Australia and assess whether these inequalities varied by year of diagnosis, age at diagnosis, time since diagnosis and sex. Cases diagnosed with a first primary cancer in 2001-2015 were identified using the Victorian Cancer Registry and followed to the end of 2016. Five-year net survival and the excess risk of death due to a cancer diagnosis were estimated. People living in more disadvantaged areas had lower five-year survival than residents of less disadvantaged regions for 21 of 29 cancer types: head and neck, oesophagus, stomach, colorectum, anus/anal canal, liver, gallbladder/biliary tract, pancreas, lung, melanoma, connective/soft tissue, female breast, ovary, prostate, kidney, bladder, brain and central nervous system, unknown primary, non-Hodgkin lymphoma, multiple myeloma and leukemia. The observed lower survival in more deprived regions persisted over time, except head and neck cancer, for which the gap in survival has widened. Socio-economic inequalities in survival decreased with increasing age at diagnosis for cancers of connective/soft tissue, bladder and unknown primary. For colorectal cancer, the observed survival disadvantage in lower socio-economic regions was greater for men than for women, while for brain and central nervous system tumours, it was larger for women. Cancer survival is generally lower for residents of more socio-economically disadvantaged areas. Identifying the underlying reasons for these inequalities is important and may help to identify effective interventions to increase survival for underprivileged cancer patients.

To test the hypothesis that more frequent consumption of sugar-sweetened soft drinks would be associated with increased risk of obesity-related cancers. Associations for artificially sweetened soft drinks were assessed for comparison. Prospective cohort study with cancers identified by linkage to cancer registries. At baseline, participants completed a 121-item FFQ including separate questions about the number of times in the past year they had consumed sugar-sweetened or artificially sweetened soft drinks. Anthropometric measurements, including waist circumference, were taken and questions about smoking, leisure-time physical activity and intake of alcoholic beverages were completed. The Melbourne Collaborative Cohort Study (MCCS) is a prospective cohort study which recruited 41 514 men and women aged 40-69 years between 1990 and 1994. A second wave of data collection occurred in 2003-2007. Data for 35 593 participants who developed 3283 incident obesity-related cancers were included in the main analysis. Increasing frequency of consumption of both sugar-sweetened and artificially sweetened soft drinks was associated with greater waist circumference at baseline. For sugar-sweetened soft drinks, the hazard ratio (HR) for obesity-related cancers increased as frequency of consumption increased (HR for consumption >1/d v. 1/d v. <1/month=1·00; 95 % CI 0·79, 1·27; P-trend=0·61). Our results add to the justification to minimise intake of sugar-sweetened soft drinks.

AbstractObjectiveTo assess the association of low socioeconomic status and risk factors for non-communicable diseases (diabetes, high alcohol intake, high blood pressure, obesity, physical inactivity, smoking) with loss of physical functioning at older ages.DesignMulti-cohort population based study.Setting37 cohort studies from 24 countries in Europe, the United States, Latin America, Africa, and Asia, 1990-2017.Participants109 107 men and women aged 45-90 years.Main outcome measurePhysical functioning assessed using the walking speed test, a valid index of overall functional capacity. Years of functioning lost was computed as a metric to quantify the difference in walking speed between those exposed and unexposed to low socioeconomic status and risk factors.ResultsAccording to mixed model estimations, men aged 60 and of low socioeconomic status had the same walking speed as men aged 66.6 of high socioeconomic status (years of functioning lost 6.6 years, 95% confidence interval 5.0 to 9.4). The years of functioning lost for women were 4.6 (3.6 to 6.2). In men and women, respectively, 5.7 (4.4 to 8.1) and 5.4 (4.3 to 7.3) years of functioning were lost by age 60 due to insufficient physical activity, 5.1 (3.9 to 7.0) and 7.5 (6.1 to 9.5) due to obesity, 2.3 (1.6 to 3.4) and 3.0 (2.3 to 4.0) due to hypertension, 5.6 (4.2 to 8.0) and 6.3 (4.9 to 8.4) due to diabetes, and 3.0 (2.2 to 4.3) and 0.7 (0.1 to 1.5) due to tobacco use. In analyses restricted to high income countries, the number of years of functioning lost attributable to low socioeconomic status by age 60 was 8.0 (5.7 to 13.1) for men and 5.4 (4.0 to 8.0) for women, whereas in low and middle income countries it was 2.6 (0.2 to 6.8) for men and 2.7 (1.0 to 5.5) for women. Within high income countries, the number of years of functioning lost attributable to low socioeconomic status by age 60 was greater in the United States than in Europe. Physical functioning continued to decline as a function of unfavourable risk factors between ages 60 and 85. Years of functioning lost were greater than years of life lost due to low socioeconomic status and non-communicable disease risk factors.ConclusionsThe independent association between socioeconomic status and physical functioning in old age is comparable in strength and consistency with those for established non-communicable disease risk factors. The results of this study suggest that tackling all these risk factors might substantially increase life years spent in good physical functioning.

Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause. A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias. The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.

The burden of chronic obstructive pulmonary disease (COPD) is increasing, yet there are limited data on early life risk factors. To investigate the role of childhood lung function in adult COPD phenotypes. Prebronchodilator spirometry was performed for a cohort of 7-year-old Tasmanian children (n = 8,583) in 1968 who were resurveyed at 45 years, and a selected subsample (n = 1,389) underwent prebronchodilator and post-bronchodilator spirometry. For this analysis, COPD was spirometrically defined as a post-bronchodilator FEV /FVC less than the lower limit of normal. Asthma-COPD overlap syndrome (ACOS) was defined as the coexistence of both COPD and current asthma. Associations between childhood lung function and asthma/COPD/ACOS were examined using multinomial regression. At 45 years, 959 participants had neither current asthma nor COPD (unaffected), 269 had current asthma alone, 59 had COPD alone, and 68 had ACOS. The reweighted prevalence of asthma alone was 13.5%, COPD alone 4.1%, and ACOS 2.9%. The lowest quartile of FEV at 7 years was associated with ACOS (odds ratio, 2.93; 95% confidence interval, 1.32-6.52), but not COPD or asthma alone. The lowest quartile of FEV /FVC ratio at 7 years was associated with ACOS (odds ratio, 16.3; 95% confidence interval, 4.7-55.9) and COPD (odds ratio, 5.76; 95% confidence interval, 1.9-17.4), but not asthma alone. Being in the lowest quartile for lung function at age 7 may have long-term consequences for the development of COPD and ACOS by middle age. Screening of lung function in school age children may identify a high-risk group that could be targeted for intervention. Further research is needed to understand possible modifiers of these associations and develop interventions for children with impaired lung function.

Current evidence on the association between body mass index (BMI) and age at menopause remains unclear. We investigated the relationship between BMI and age at menopause using data from 11 prospective studies. A total of 24,196 women who experienced menopause after recruitment was included. Baseline BMI was categorised according to the WHO criteria. Age at menopause, confirmed by natural cessation of menses for ≥ 12 months, was categorised as < 45 years (early menopause), 45-49, 50-51 (reference category), 52-53, 54-55, and ≥ 56 years (late age at menopause). We used multinomial logistic regression models to estimate multi variable relative risk ratios (RRRs) and 95% confidence intervals (CI) for the associations between BMI and age at menopause. The mean (standard deviation) age at menopause was 51.4 (3.3) years, with 2.5% of the women having early and 8.1% late menopause. Compared with those with normal BMI (18.5-24.9 kg/m²), underweight women were at a higher risk of early menopause (RRR 2.15, 95% CI 1.50-3.06), while overweight (1.52, 1.31-1.77) and obese women (1.54, 1.18-2.01) were at increased risk of late menopause. Overweight and obesity were also significantly associated with around 20% increased risk of menopause at ages 52-53 and 54-55 years. We observed no association between underweight and late menopause. The risk of early menopause was higher among obese women albeit not significant (1.23, 0.89-1.71). Underweight women had over twice the risk of experiencing early menopause, while overweight and obese women had over 50% higher risk of experiencing late menopause.

Background Tumour DNA methylation has been investigated as a potential marker for breast cancer survival, but findings often lack replication across studies. Methods This study sought to replicate previously reported associations for individual CpG sites and multi-CpG signatures using an Australian sample of 425 women with breast cancer from the Melbourne Collaborative Cohort Study (MCCS). Candidate methylation sites (N = 22) and signatures (N = 3) potentially associated with breast cancer survival were identified from five prior studies that used The Cancer Genome Atlas (TCGA) methylation dataset, which shares key characteristics with the MCCS: comparable sample size, tissue type (formalin-fixed paraffin-embedded; FFPE), technology (Illumina HumanMethylation450 array), and participant characteristics (age, ancestry, and disease subtype and severity). Cox proportional hazard regression analyses were conducted to assess associations between these markers and both breast cancer-specific survival and overall survival, adjusting for relevant participant characteristics. Results Our findings revealed partial replication for both individual CpG sites (9 out of 22) and multi-CpG signatures (2 out of 3). These associations were maintained after adjustment for participant characteristics and were stronger for breast cancer-specific mortality than for overall mortality. In fully-adjusted models, strong associations were observed for a CpG in PRAC2 (per standard deviation [SD], HR = 1.67, 95%CI: 1.24–2.25) and a signature based on 28 CpGs developed using elastic net (per SD, HR = 1.48, 95%CI: 1.09–2.00). Conclusions While further studies are needed to confirm and expand on these findings, our study suggests that DNA methylation markers hold promise for improving breast cancer prognostication.

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). 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. 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.

Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk. DNA methylation is associated with breast cancer risk. Here the authors measure DNA methylation in the blood of individuals from 25 Australian families with multiple cases of breast cancer but not known mutations associated with breast cancer risk to identify possible heritable methylation markers.

ObjectiveMost studies investigating the association between resting heart rate (RHR) and mortality have focused on cardiovascular disease (CVD) mortality, and measured RHR at only one time point. We aimed to assess associations of RHR and changes in RHR over approximately a decade with overall and cause-specific mortality.MethodsWe used data from participants in the Melbourne Collaborative Cohort Study with RHR measures at baseline (1990–1994; n=41 386; 9846 deaths) and at follow-up (2003–2007; n=21 692; 2818 deaths). RHR measures were taken by trained staff, using Dinamap monitors. Cox models were used to estimate HR and 95% CI for the associations between RHR and mortality. Vital status and cause of death were ascertained until August 2015 and December 2013, respectively.ResultsAfter adjustment for confounders, including blood pressure and known medical conditions but not arrhythmias or atrial fibrillation, RHR was associated with a higher risk of death of similar magnitude for CVD (HR per 10 beats per minute (bpm)=1.11, 95% CI 1.07 to 1.16), cancer (HR=1.10, 95% CI 1.06 to 1.13) and other causes (HR=1.20, 95% CI 1.16 to 1.25). Higher mortality was observed for most cancer sites, including breast (HR=1.16, 95% CI 1.03 to 1.31), colorectal (HR=1.18, 95% CI 1.08 to 1.29), kidney (HR=1.27, 95% CI 1.03 to 1.57) and lung cancer (HR=1.19, 95% CI 1.10 to 1.29). Temporal increases in RHR were associated with higher mortality, particularly for individuals whose RHR increased by more than 15 bpm.ConclusionsRHR and changes in RHR over a decade are associated with mortality risk, including from causes other than CVD such as breast, colorectal or lung cancer. Monitoring of RHR may have utility in identifying individuals at higher mortality risk.