The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them “age acceleration.” We aimed to assess the ...associations of age acceleration with risk of and survival from seven common cancers. Seven case–control studies of DNA methylation and colorectal, gastric, kidney, lung, prostate and urothelial cancer and B‐cell lymphoma nested in the Melbourne Collaborative Cohort Study were conducted. Cancer cases, vital status and cause of death were ascertained through linkage with cancer and death registries. Conditional logistic regression and Cox models were used to estimate odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals (CI) for associations of five age acceleration measures derived from the Human Methylation 450 K Beadchip assay with cancer risk (N = 3,216 cases) and survival (N = 1,726 deaths), respectively. Epigenetic aging was associated with increased cancer risk, ranging from 4% to 9% per five‐year age acceleration for the 5 measures considered. Heterogeneity by study was observed, with stronger associations for risk of kidney cancer and B‐cell lymphoma. An associated increased risk of death following cancer diagnosis ranged from 2% to 6% per five‐year age acceleration, with no evidence of heterogeneity by cancer site. Cancer risk and mortality were increased by 15–30% for the fourth versus first quartile of age acceleration. DNA methylation‐based measures of biological aging are associated with increased cancer risk and shorter cancer survival, independently of major health risk factors.
What's new?
Aging is associated with profound changes in DNA methylation levels. These can be used to build accurate age predictors (“epigenetic clocks”) that deviate from chronological age by only a few years, a phenomenon named “age acceleration”. In this study of seven types of cancer, the authors found that age acceleration was associated with both increased cancer risk and decreased cancer survival, independently of major health risk factors. These results support the usefulness of methylation markers of biological aging as a tool to predict health outcomes and may provide valuable insight into the relationship between aging and cancer.
Summary Background Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not ...suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy. Methods In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov ( NCT00110162 ). Findings Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3–6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5–91·5) in the delayed therapy arm versus 91·2% (84·2–95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30–1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm. Interpretation Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options. Funding Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.
The associations between intake of or circulating fatty acids and risk of colorectal cancer (CRC) are unclear. We examined prospectively the associations between dietary or biomarker fatty acids and ...CRC. For 41,514 men and women, aged 40–69 years, baseline (1990–94) dietary intakes of fatty acids were estimated using a food frequency questionnaire and plasma phospholipid (PPL) fatty acids were measured for 4,205 participants including 395 CRC cases, according to a case‐cohort design. Hazard ratios were computed using Cox regression adjusting for education, alcohol intake, smoking status, physical activity and total energy intake; and stratified for gender, ethnicity and family history of cancer, with age as the time scale. We assessed the heterogeneity of associations with colon and rectal cancers. PPL saturated fatty acids (SFAs) were positively associated with CRC risk, while total n‐3 polyunsaturated fatty acids (PUFA) and long chain marine n‐3 PUFAs showed inverse associations, significant only for 22:5 n‐3. No significant associations were observed for dietary fatty acid intakes but positive associations with CRC of borderline significance were seen for both dietary and PPL linoleic acid. Positive associations with dietary palmitic acid (16:0), MUFAs and n‐6 PUFAs were seen for rectal but not colon cancers. PPL 22:6 n‐3 was inversely associated with rectal cancer. Limiting intakes of SFAs and MUFAs could be assisted by following existing guidelines to limit red and processed meats which are important sources in the Australian diet. Our observations regarding linoleic acid should be examined further.
What's new?
While there is considerable evidence that diet is associated with colorectal cancer (CRC) risk, the associations for specific fatty acids remain unclear. Here, the authors prospectively examine associations between dietary intake estimates or plasma phospholipids (PPL) estimates of fatty acids and incident CRC. PPL saturated fat (SF) is positively associated with incident CRC and dietary SF with rectal cancer, while long chain n‐3 fats are inversely associated with both. Following guidelines to limit red and processed meat would help reduce saturated fatty acids intake; the adverse association with linoleic acid, found in margarines and vegetable oils, requires further confirmation.
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.
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.
What's new?
Alcoholic beverages are a known risk factor for oral cavity, pharynx, larynx, esophagus, liver, colorectal and breast cancers. Unlike most previous studies of alcohol intake and cancer risk, here the authors examined associations of longitudinal drinking trajectories across the lifespan. Compared with lifelong non‐drinking, they observed an increased cancer risk associated with heavy drinking during early adulthood, even when the intake had ceased by middle age, and with drinking that increased during the life‐course. The findings of this large prospective study point to critical timelines related to alcohol‐related cancer etiology and prevention during the adult lifespan.
Cereal foods are consumed globally and are important sources of polyphenols with potential health benefits, yet dietary intakes are unclear. We aimed to calculate the dietary intakes of polyphenols ...from cereal foods in the Melbourne Collaborative Cohort Study (MCCS), and describe intakes by demographic and lifestyle factors. We estimated intakes of alkylresorcinols, lignans and phenolic acids in n = 39,892 eligible MCCS participants, using baseline dietary data (1990-1994) from a 121-item FFQ containing 17 cereal foods, matched to a polyphenol database developed from published literature and Phenol-Explorer Database. Intakes were estimated within groups according to lifestyle and demographic factors. The median (25th-75th percentile) intake of total polyphenols from cereal foods was 86.9 mg/day (51.4-155.8). The most consumed compounds were phenolic acids, with a median intake of 67.1 mg (39.5-118.8), followed by alkylresorcinols of 19.7 mg (10.8-34.6). Lignans made the smallest contribution of 0.50 mg (0.13-0.87). Higher polyphenol intakes were associated with higher relative socio-economic advantage and prudent lifestyles, including lower body mass index (BMI), non-smoking and higher physical activity scores. The findings based on polyphenol data specifically matched to the FFQ provide new information on intakes of cereal polyphenols, and how they might vary according to lifestyle and demographic factors.
Studies investigating the association of food and nutrient consumption with the risk of urothelial cell carcinoma (UCC) have produced mixed results. We used three common dietary scores, the ...Mediterranean Diet Score (MDS), the Alternate Healthy Eating Index 2010 (AHEI‐2010) and the Dietary Inflammatory Index (DII) to assess the evidence of an association between diet and the risk of UCC. Over a median follow‐up time of 21.3 years, 379 incident UCC cases were diagnosed. Dietary scores were calculated using data from a 121‐item food frequency questionnaire administered at baseline. We used Cox models to compute hazard ratios (HR) for the association between dietary scores (per one standard deviation) and UCC risk. In order to reflect overall adherence to a healthy diet, a metascore was constructed by summing the quintiles of each of the three scores. None of the dietary scores was associated with the risk of UCC overall. A healthier diet was found to be inversely associated with the risk of invasive (MDS: HR = 0.86, 95% CI: 0.74–1.00, metascore: HR = 0.84, 95% CI: 0.71–0.98), but not superficial disease (heterogeneity between subtypes p = 0.04 and p = 0.03, respectively). Results were consistent but weaker for the DII and the AHEI‐2010. We found some evidence of effect modification by smoking, in particular for the metascore (Current: HR = 0.77, 95% CI: 0.58–1.01, Former: HR = 0.77, 95% CI: 0.64–0.92, Never: HR = 1.01, 95% CI: 0.81–1.26, p for heterogeneity = 0.05). A healthy diet may be protective against the risk of invasive, but not superficial, UCC. Promoting healthy dietary habits may help lower the risk of invasive UCC, especially for current and former smokers.
What's new?
When components of the food we eat interact with the lining of the urethra on their way out, they can influence urothelial cell carcinoma. Various studies have tried to quantify the impact of individual nutrients on UCC risk; this study instead focused on the diet as a whole. Each person's dietary pattern received a score on three separate scales that reflect different philosophies of healthy eating, but the scores did not correlate with overall urothelial cell cancer risk. The authors did find that people with a healthier diet had a lower risk of invasive cancers, and healthier eating especially benefitted smokers.
Consumption of sugary drinks increases the risk of obesity. Previously, we reported a positive association between sugar‐sweetened soft drink consumption and obesity‐related cancer, but this ...association was not fully explained by obesity; in contrast, we found no association for consumption of artificially sweetened soft drinks. Our aim was to determine whether the consumption of sugar‐sweetened or artificially sweetened soft drinks was associated with cancers other than those currently identified as being related to obesity. We used data from the Melbourne Collaborative Cohort Study. Participants completed a 121‐item food‐frequency questionnaire at baseline including separate questions about the number of times in the past year they had consumed sugar‐sweetened and artificially sweetened soft drinks. Cox regression models were fitted to estimate hazard ratios and 95% confidence intervals for the risk of cancers not related to obesity. During 19 years of follow‐up, there were 35,109 eligible participants who developed 4,789 cancers not related to obesity. There was no association between frequency of consuming sugar‐sweetened soft drinks and the risk of these cancers, but an unexpected positive association was observed for consumption of artificially sweetened soft drinks. Although, we did not find an association with sugar‐sweetened soft drinks, we previously reported a positive association with obesity‐related cancers, not fully explained by obesity. These findings leave unresolved the question of whether consumption of sugar‐sweetened soft drinks influences cancer risk independently of their influence on body size.
What's new?
Previously, the authors reported a positive association between consumption of sugar‐sweetened soft drinks and risk of obesity‐related cancers, but this association was not completely explained by obesity. In this prospective study, they investigated sugar‐sweetened soft drink consumption and non‐obesity‐related cancers and found no association. An unexpected positive association was observed with artificially‐sweetened soft drinks. Even though these findings leave unresolved whether consumption of sugar‐ sweetened soft drinks influences cancer risk independently of their association with body size, the work still supports recommendations to limit soft drink consumption. More research is needed to confirm the long‐term safety of artificially‐sweetened soft drinks.
Abstract
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.
Higher levels of time spent sitting (sedentary behavior) contribute to adverse health outcomes, including earlier death. This effect may be modified by other lifestyle factors. We examined the ...association of television viewing (TV), a common leisure-time sedentary behavior, with all-cause mortality, and whether this is modified by body mass index (BMI), physical activity, smoking, alcohol intake, soft drink consumption, or diet-associated inflammation.
Using data from participants in the Melbourne Collaborative Cohort Study, flexible parametric survival models assessed the time-dependent association of self-reported TV time (three categories: < 2 h/day, 2-3 h/day, > 3 h/day) with all-cause mortality. Interaction terms were fitted to test whether there was effect modification of TV time by the other risk factors.
From 19,570 participants, 4,417 deaths were reported over a median follow up of 14.5 years. More TV time was associated with earlier mortality; however, this relationship diminished with increasing age. The hazard ratio (HR) and 95% confidence interval (95% CI) for > 3 h/day compared with < 2 h/day of TV time was 1.34 (1.16, 1.55) at 70 years, 1.14 (1.04, 1.23) at 80 years, and 0.95 (0.84, 1.06) at 90 years. The TV time/mortality relationship was more evident in participants who were physically inactive (compared with active; p for interaction < 0.01) or had a higher dietary inflammatory index score (compared with a lower score; p for interaction = 0.03). No interactions were detected between TV time and BMI, smoking, alcohol intake, nor soft-drink consumption (all p for interaction > 0.16).
The relationship between TV time and all-cause mortality may change with age. It may also be more pronounced in those who are otherwise inactive or who have a pro-inflammatory diet.
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