Melbourne School of Population and Global Health - Research Publications
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ItemNo Preview AvailableGenetic and Environmental Causes of Variation in an Automated Breast Cancer Risk Factor Based on Mammographic Textures(AMER ASSOC CANCER RESEARCH, 2024-02-06)BACKGROUND: Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. METHODS: We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants. RESULTS: There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%). CONCLUSION: Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins. IMPACT: Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens.
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ItemNo Preview AvailableAdherence to 2018 WCRF/AICR Cancer Prevention Recommendations and Risk of Cancer: The Melbourne Collaborative Cohort Study(AMER ASSOC CANCER RESEARCH, 2024-01-09)BACKGROUND: We examined associations between adherence to adaptations of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and total, exposure-related and site-specific cancer risk. METHODS: A total of 20,001 participants ages 40 to 69 years at enrollment into the Melbourne Collaborative Cohort Study in 1990 to 1994, who had diet, body size, and lifestyle reassessed in 2003 to 2007 ("baseline"), were followed-up through June 2021. We constructed diet and standardized lifestyle scores based on core WCRF/AICR recommendations on diet, alcohol intake, body size and physical activity, and additional scores incorporating weight change, sedentary behavior, and smoking. Associations with cancer risk were estimated using Cox regression, adjusting for confounders. RESULTS: During follow-up (mean = 16 years), 4,710 incident cancers were diagnosed. For highest quintile ("most adherent") of the standardized lifestyle score, compared with lowest ("least adherent"), a HR of 0.82 [95% confidence interval (CI): 0.74-0.92] was observed for total cancer. This association was stronger with smoking included in the score (HR = 0.74; 95% CI: 0.67-0.81). A higher score was associated with lower breast and prostate cancer risk for the standardized score, and with lung, stomach, rectal, and pancreatic cancer risk when the score included smoking. Our analyses identified alcohol use, waist circumference and smoking as key drivers of associations with total cancer risk. CONCLUSIONS: Adherence to WCRF/AICR cancer prevention recommendations is associated with lower cancer risk. IMPACT: With <0.2% of our sample fully adherent to the recommendations, the study emphasizes the vast potential for preventing cancer through modulation of lifestyle habits.
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ItemModifiable lifestyle risk factors and survival after diagnosis with multiple myeloma(TAYLOR & FRANCIS LTD, 2023-10-03)BACKGROUND: While remaining incurable, median overall survival for MM now exceeds 5 years. Yet few studies have investigated how modifiable lifestyle factors influence survival. We investigate whether adiposity, diet, alcohol, or smoking are associated with MM-related fatality. RESEARCH DESIGN AND METHODS: We recruited 760 incident cases of MM via cancer registries in two Australian states during 2010-2016. Participants returned questionnaires on health and lifestyle. Follow-up ended in 2020. Flexible parametric survival models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lifestyle exposures and risk of all-cause and MM-specific fatality. RESULTS: Higher pre-diagnosis Alternative Healthy Eating Index (AHEI) scores were associated with reduced MM-specific fatality (per 10-unit score, HR = 0.84, 95%CI = 0.70-0.99). Pre-diagnosis alcohol consumption was inversely associated with MM-specific fatality, compared with nondrinkers (0.1-20 g per day, HR = 0.59, 95%CI = 0.39-0.90; >20 g per day, HR = 0.67, 95%CI = 0.40-1.13). Tobacco smoking was associated with increased all-cause fatality compared with never smoking (former smokers: HR = 1.44, 95%CI = 1.10-1.88; current smokers: HR = 1.30, 95%CI = 0.80-2.10). There was no association between pre-enrollment body mass index (BMI) and MM-specific or all-cause fatality. CONCLUSIONS: Our findings support established recommendations for healthy diets and against smoking. Higher quality diet, as measured by the AHEI, may improve survival post diagnosis with MM.
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ItemNo Preview AvailableCausal relationships between breast cancer risk factors based on mammographic features(BMC, 2023-10-25)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.
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ItemNo Preview AvailableFamily history and breast cancer risk for Asian women: a systematic review and meta-analysis(BMC, 2023-07-03)BACKGROUND: Studies of women of European ancestry have shown that the average familial relative risk for first-degree relatives of women with breast cancer is approximately twofold, but little is known for Asian women. We aimed to provide evidence for the association between family history and breast cancer risk for Asian women by systematically reviewing published literature. METHODS: Studies reporting the familial relative risk of breast cancer for Asian women were searched in three online databases and complemented by a manual search. Odds ratios (ORs) for the association between family history and breast cancer risk were pooled across all included studies and by subgroups in terms of the type of family history, age, menopausal status and geographical region. RESULTS: The pooled OR for women who have a first-degree relative with breast cancer was 2.46 (95% confidence interval [CI]: 2.03, 2.97). There was no evidence that the familial risk differed by the type of affected relative (mother versus sisters), the woman's age (< 50 years versus ≥ 50 years), menopausal status (pre versus post) and geographical region (East and Southeast Asia versus other regions) (all P > 0.3). The pooled ORs for women of Asian ancestry with a family history in any relative were similar for those living in non-Asian countries (2.26, 95% CI: 1.42, 3.59) compared with those living in Asian countries (2.18, 95% CI: 1.85, 2.58). CONCLUSIONS: Family history of breast cancer is associated with an approximately twofold relative risk of breast cancer for Asian women, which is of similar magnitude to that observed for women of European ancestry. This implies that similar familial factors are implicated in breast cancer risk between women of European and Asian ancestries. Genetic factors are likely to play a substantial role in explaining the breast cancer familial risk for Asian women, as similar risks were observed across different living environments and cultures.
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ItemNo Preview AvailablePre-diagnostic cigarette smoking and risk of second primary cancer: The Melbourne Collaborative Cohort Study(ELSEVIER SCI LTD, 2023-08)Enhanced survival following a diagnosis of cancer has led to a steep rise in the number of individuals diagnosed with a second primary cancer. We examined the association between pre-cancer cigarette smoking and risk of second cancer in 9785 participants diagnosed with first invasive cancer after enrolment in the Melbourne Collaborative Cohort Study. Follow-up was from date of first invasive cancer until diagnosis of second primary invasive cancer, death, or 31 July 2019, whichever came first. Data on cigarette smoking was collected at enrolment (1990-94) along with information on other lifestyle factors including body size, alcohol intake and diet. We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for incident second cancer with several smoking measures, adjusted for potential confounders. After a mean follow-up of 7.3 years, 1658 second cancers were identified. All measures of smoking were associated with increased risk of second cancer. We observed a 44 % higher risk of second cancer for smokers of ≥ 20 cigarettes/day (HR=1.44, 95 % CI: 1.18-1.76), compared with never smokers. We also observed dose-dependent associations with number of cigarettes smoked (HR=1.05 per 10 cigarettes/day, 95 % CI: 1.01-1.09) and duration of smoking (HR=1.07 per 10 years, 95 % CI: 1.03-1.10). The risk of second cancer increased by 4 % per 10 pack-years of smoking (HR=1.04, 95 % CI: 1.02-1.06; p < 0.001). There was suggestive evidence of stronger associations with number of cigarettes smoked and pack-years of smoking for women (pinteraction<0.05), particularly for the highest risk categories of both variables. These associations with pre-diagnostic smoking were markedly stronger for second cancers known to be smoking-related than for others (phomogeneity<0.001). Our findings for pre-diagnostic cigarette smoking indicated increased risk of second primary cancer for cancer sites considered smoking-related, highlighting the importance of assessing smoking habits in cancer survivors.
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ItemNo Preview AvailableEvaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry(CELL PRESS, 2023-07-06)Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.
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ItemNo Preview AvailableVariance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks(OXFORD UNIV PRESS, 2023-10-05)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(rΔ2). 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.
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ItemNo Preview AvailableThe future burden of oesophageal and stomach cancers attributable to modifiable behaviours in Australia: a pooled cohort study(SPRINGERNATURE, 2023-04-06)BACKGROUND: We quantified the individual and joint contribution of contemporaneous causal behavioural exposures on the future burden of oesophageal and stomach cancers and their subtypes and assessed whether these burdens differ between population groups in Australia, as such estimates are currently lacking. METHODS: We combined hazard ratios from seven pooled Australian cohorts (N = 367,058) linked to national cancer and death registries with exposure prevalence from the 2017-2018 National Health Survey to estimate Population Attributable Fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death. RESULTS: Current and past smoking explain 35.2% (95% CI = 11.7-52.4%), current alcohol consumption exceeding three drinks/day 15.7% (95% CI = 0.9-28.4%), and these exposures jointly 41.4% (95% CI = 19.8-57.3%) of oesophageal squamous cell carcinomas in Australia. Current and past smoking contribute 38.2% (95% CI = 9.4-57.9%), obesity 27.0% (95% CI = 0.6-46.4%), and these exposures jointly 54.4% (95% CI = 25.3-72.1%) of oesophageal adenocarcinomas. Overweight and obesity explain 36.1% (95% CI = 9.1-55.1%), current and past smoking 24.2% (95% CI = 4.2-40.0%), and these exposures jointly 51.2% (95% CI = 26.3-67.8%) of stomach cardia cancers. Several population groups had a significantly higher smoking-attributable oesophageal cancer burden, including men and those consuming excessive alcohol. CONCLUSIONS: Smoking is the leading preventable behavioural cause of oesophageal cancers and overweight/obesity of stomach cancers.
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ItemNo Preview AvailableHeritable methylation marks associated with prostate cancer risk.(Springer Science and Business Media LLC, 2023-07)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.