Abstract
Background
Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty ...risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex.
Methods
We analyzed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7 573 692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma. Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex.
Results
We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL, and 20q13.33 GMEB2 (P < .05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P = .0024) with the association being nominally significant for both sexes (P < .05).
Conclusions
Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analyzing glioma GWAS by sex. A better understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment.
Without preventive interventions, women with germline pathogenic variants in
or
have high lifetime risks for breast cancer and tubo-ovarian cancer. The increased risk for breast cancer starts at a ...considerably younger age than that for tubo-ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is effective in reducing tubo-ovarian cancer risk for
and
mutation carriers, but whether it reduces breast cancer risk is less clear. All studies of rrBSO and breast cancer risk are observational in nature and subject to various forms of bias and confounding, thus limiting conclusions that can be drawn about causation. Early studies supported a statistically significant protective association for rrBSO on breast cancer risk, which is reflected by several international guidelines that recommend consideration of premenopausal rrBSO for breast cancer risk reduction. However, these historical studies were hampered by the presence of several important biases, including immortal person-time bias, confounding by indication, informative censoring, and confounding by other risk factors, which may have led to overestimation of any protective benefit. Contemporary studies, specifically designed to reduce some of these biases, have yielded contradictory results. Taken together, there is no clear and consistent evidence for a role of premenopausal rrBSO in reducing breast cancer risk in
or
mutation carriers.
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.
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.
Abstract
Background
Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian ...randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits.
Methods
Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity.
Results
Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08–1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed.
Conclusions
This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.
Background: To evaluate the use of stereotactic body radiation therapy (SBRT) for spine metastases and the associated factors in Australia. Methods: The Victorian Radiotherapy Minimum Dataset, which ...captures all episodes of radiotherapy delivered in the state of Victoria, was accessed to evaluate the patterns and trends of SBRT for spine metastases. The primary outcome was SBRT use and associated factors. Results: There were 6244 patients who received 8861 courses of radiotherapy for spine metastases between 2012 and 2017. Of these, 277 (3%) courses were SBRT, which increased from 0.4% in 2012 to 5% in 2017 (P-trend < 0.001). There was a higher proportion of SBRT use in patients with prostate cancer (6%) and melanoma (4%) compared to other cancers (2–3%) (p < 0.001). Patients from the highest socioeconomic quintiles (5%) were more likely to be treated with SBRT compared to patients from the lowest socioeconomic quintiles (3%) (p < 0.001). There was a higher proportion of SBRT use in private radiotherapy centres (6%) compared to public radiotherapy centres (1%) (p < 0.001). No spine SBRT was delivered in regional centres. In multivariate analyses, the year of treatment, age, primary cancers and radiotherapy centres were independently associated with SBRT use. Conclusion: This is the first Australian population-based study quantifying the increasing use of spine SBRT; however, the overall use of spine SBRT remains low. We anticipate an ongoing increase in spine SBRT, as spine SBRT gradually becomes the standard-of-care treatment for painful spine metastases.
The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis ...and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990–1994) and wave 2 (2003–2007). We included participants diagnosed to 31 August 2015 with incident stages I–III CRC within 10‐years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC‐specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow‐up (average 9.0 years). Exercise (non‐occupational/leisure‐time) was associated with higher CRC‐specific survival for stage II (HR = 0.25, 95% CI: 0.10–0.60) but not stages I/III disease (p for interaction = 0.01), and possibly for colon and KRAS wild‐type tumors. Waist circumference was inversely associated with CRC‐specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08–1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC‐specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre‐diagnostic predictors of survival following CRC that may have clinical and public health relevance.
What's new?
While survival following colorectal cancer (CRC) is improving, it remains unclear whether increasing survival is linked to specific health or lifestyle factors that were present before or after CRC diagnosis. In our study, based on data from the Melbourne Collaborative Cohort Study (MCCS), exercise prior to diagnosis was associated with higher CRC‐specific survival specifically for stage II patients. Waist circumference, by contrast, was associated with reduced CRC‐specific survival, while cigarette smoking was associated with lower overall survival. Cigarette smoking was also weakly linked to decreased survival in BRAF‐mutated CRC. No associations were detected between CRC survival and alcohol intake.
Abstract
Background
Rigorous evaluation of the calibration and discrimination of breast-cancer risk-prediction models in prospective cohorts is critical for applications under clinical guidelines. We ...comprehensively evaluated an integrated model incorporating classical risk factors and a 313-variant polygenic risk score (PRS) to predict breast-cancer risk.
Methods
Fifteen prospective cohorts from six countries with 239 340 women (7646 incident breast-cancer cases) of European ancestry aged 19–75 years were included. Calibration of 5-year risk was assessed by comparing expected and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50–70 years in those countries was evaluated by the proportion of women and future cases crossing clinically relevant risk thresholds.
Results
Among women <50 years old, the median (range) expected-to-observed ratio for the integrated model across 15 cohorts was 0.9 (0.7–1.0) overall and 0.9 (0.7–1.4) at the highest-risk decile; among women ≥50 years old, these were 1.0 (0.7–1.3) and 1.2 (0.7–1.6), respectively. The proportion of women identified above a 3% 5-year risk threshold (used for recommending risk-reducing medications in the USA) ranged from 7.0% in Germany (∼841 000 of 12 million) to 17.7% in the USA (∼5.3 of 30 million). At this threshold, 14.7% of US women were reclassified by adding the PRS to classical risk factors, with identification of 12.2% of additional future cases.
Conclusion
Integrating a 313-variant PRS with classical risk factors can improve the identification of European-ancestry women at elevated risk who could benefit from targeted risk-reducing strategies under current clinical guidelines.
Abstract
Epigenetic age is an emerging marker of health that is highly predictive of disease and mortality risk. There is a lack of evidence on whether lifestyle changes are associated with changes ...in epigenetic aging. We used data from 1 041 participants in the Melbourne Collaborative Cohort Study with blood DNA methylation measures at baseline (1990–1994, mean age: 57.4 years) and follow-up (2003–2007, mean age: 68.8 years). The Alternative Healthy Eating Index-2010 (AHEI-2010), the Mediterranean Dietary Score, and the Dietary Inflammatory Index were used as measures of diet quality, and weight, waist circumference, and waist-to-hip ratio as measures of body size. Five age-adjusted epigenetic aging measures were considered: GrimAge, PhenoAge, PCGrimAge, PCPhenoAge, and DunedinPACE. Multivariable linear regression models including restricted cubic splines were used to assess the cross-sectional and longitudinal associations of body size and diet quality with epigenetic aging. Associations between weight and epigenetic aging cross-sectionally at both time points were positive and appeared greater for DunedinPACE (per SD: β ~0.24) than for GrimAge and PhenoAge (β ~0.10). The longitudinal associations with weight change were markedly nonlinear (U-shaped) with stable weight being associated with the lowest epigenetic aging at follow-up, except for DunedinPACE, for which only weight gain showed a positive association. We found negative, linear associations for AHEI-2010 both cross-sectionally and longitudinally. Other adiposity measures and dietary scores showed similar results. In middle-aged to older adults, declining diet quality and weight gain may increase epigenetic age, while the association for weight loss may require further investigation. Our study sheds light on the potential of weight management and dietary improvement in slowing aging processes.
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