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Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case-cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case-control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m 2 compared to women with BMI 18.5-25 kg/m 2 , the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05-2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43-2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11-2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68-1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity-breast cancer relationship but does not explain all of the association., (© 2019 UICC.)

Measures of biological age based on blood DNA methylation, referred to as age acceleration (AA), have been developed. We examined whether AA was associated with health risk factors and overall and cause-specific mortality. At baseline (1990-1994), blood samples were drawn from 2,818 participants in the Melbourne Collaborative Cohort Study (Melbourne, Victoria, Australia). DNA methylation was determined using the Infinium HumanMethylation450 BeadChip array (Illumina Inc., San Diego, California). Mixed-effects models were used to examine the association of AA with health risk factors. Cox models were used to assess the association of AA with mortality. A total of 831 deaths were observed during a median 10.7 years of follow-up. Associations of AA were observed with male sex, Greek nationality (country of birth), smoking, obesity, diabetes, lower education, and meat intake. AA measures were associated with increased mortality, and this was only partly accounted for by known determinants of health (hazard ratios were attenuated by 20%-40%). Weak evidence of heterogeneity in the association was observed by sex (P = 0.06) and cause of death (P = 0.07) but not by other factors. DNA-methylation-based AA measures are associated with several major health risk factors, but these do not fully explain the association between AA and mortality. Future research should investigate what genetic and environmental factors determine AA.

Previous research relating lower socioeconomic status (SES) with poorer survival from colorectal cancer has varied in adjustment for confounding factors and in the use of individual-level or aggregate-level indicators of SES. We investigated the effect of SES and country of birth on survival from colorectal cancers diagnosed in participants of the Melbourne Collaborative Cohort Study. A total of 526 colorectal cancer cases diagnosed since baseline were followed from diagnosis to 1 June 2006 or death. Information on tumour site and stage, and treatments given were obtained from systematic medical record review. SES at diagnosis was assigned using both an area-based measure of social disadvantage and individual level of educational attainment. Cox regression models were used to estimate hazard ratios associated with socioeconomic disadvantage, educational attainment, and country of birth. During an average follow-up of 5.6 years from diagnosis, 230 deaths occurred, 197 from colorectal cancer. After adjusting for age, sex, tumour stage, waist circumference and adjuvant chemotherapy and radiotherapy, the hazard ratios of dying from all causes and from colorectal cancer associated with living in the least disadvantaged areas compared with most disadvantaged areas were 0.73 (95% CI 0.53-1.00, p for trend=0.06) and 0.80 (95% CI 0.57-1.12, p for trend=0.22) respectively. Further adjustment for hospital case-load, tumour characteristics, and lifestyle factors did not change the estimates materially. Level of educational attainment and country of birth were not independent predictors of the risk of dying from colorectal cancer. Despite a universal health care system in Australia, socioeconomic inequalities in survival from colorectal cancer exist, and an enduring challenge is to ensure that improvements in colorectal cancer survival are shared equally across the population.

Subjects within a family have a high probability of sharing environmental factors as well as genes. Without any previous hypothesis, familial aggregation cannot be attributed to genetic or environmental factors. In epidemiology a common measure of familial aggregation is the odds ratio (OR) evaluated from case-control studies which gives a measure of the increased risk associated with particular aspects of the family's history of disease. An analytical method is presented to model the OR of case-control studies in the presence of risk factors, genetic or environmental, that are correlated between relatives. A graphical approach that can be used to link the parameters of the model with the values of the OR is also described. The method is illustrated using the example of familial aggregation in colorectal cancer.