Publications by authors named "Roger L Milne"

416 Publications

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

PLoS Med 2021 Sep 20;18(9):e1003786. Epub 2021 Sep 20.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.

Background: 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).

Methods And Findings: 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.

Conclusions: 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.
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http://dx.doi.org/10.1371/journal.pmed.1003786DOI Listing
September 2021

Smoking methylation marks for prediction of urothelial cancer risk.

Cancer Epidemiol Biomarkers Prev 2021 Sep 14. Epub 2021 Sep 14.

Precision Medicine, School of Clinical Sciences at Monash Healh, Monash University

Background: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction.

Methods: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples, N=404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and N=440 pairs from the Women's Health Initiative (WHI) cohort, respectively. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication datasets using the area under the curve (AUC).

Results: The meta-analysis identified associations (P<4.7×10-5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations (P<0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication dataset in MCCS (N=134, odds ratio per SD [OR]=1.37, 95%CI=1.00-1.90) after confounder adjustment; AUC=0.66, compared with AUC=0.64 without methylation information. Limited evidence of replication was found in the second testing dataset in WHI (N=440, OR=1.09, 95%CI=0.91-1.30).

Conclusions: Combination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger datasets.

Impact: DNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0313DOI Listing
September 2021

Underutilisation of breast cancer prevention medication in Australia.

Breast 2021 Aug 23;60:35-37. Epub 2021 Aug 23.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia. Electronic address:

Increased implementation of proven prevention strategies is required to combat rising breast cancer incidence. We assessed use of risk reducing medication (RRMed) by Australian women at elevated breast cancer risk. Only 2.4% had ever used RRMed. Higher breast cancer risk was statistically significantly associated with use of RRMed (OR 1.82, 95%CI: 1.08-3.07, p = 0.02 for ≥30% lifetime risk compared with 16%-29% lifetime risk), but parity, education level and family history of breast cancer were not. Breast cancer prevention medications are underutilised. Efforts are needed to incorporate breast cancer risk assessment and risk management discussions into routine health assessments for women.
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http://dx.doi.org/10.1016/j.breast.2021.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399345PMC
August 2021

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Breast Cancer Res 2021 Aug 18;23(1):86. Epub 2021 Aug 18.

Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.

Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).

Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.

Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
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http://dx.doi.org/10.1186/s13058-021-01450-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371820PMC
August 2021

Changing pattern of radiation therapy for bone metastases in an Australian population-based cohort of men with prostate cancer.

Clin Genitourin Cancer 2021 Jul 10. Epub 2021 Jul 10.

Alfred Health Radiation Oncology Services, Australia; Central Clinical School, Monash University, Australia.

Introduction: To evaluate the pattern of use of single-fraction conformal radiation therapy (SF-RT) and advanced radiation therapy techniques (ART), including stereotactic body radiation therapy (SBRT), for management of bone metastases (BM) in a population-based cohort of Australian men with prostate cancer (PCa) PATIENT AND METHODS: We reviewed men with metastatic PCa who received RT for BM between 2012 and 2017 as captured in the statewide Victorian Radiotherapy Minimum Data Set (VRMDS). The primary outcomes were: proportion of RT courses using SF-RT and ART. The Cochrane-Armitage test for trend was used to evaluate the changing pattern of SF-RT and ART over time. Multivariate analyses were used to identify factors associated with the primary outcomes RESULTS: Of the 4,324 courses of palliative RT for BM, 767 (17.7%) were SF-RT, and 615 (14.2%) were ART. There was no evidence of change in SF-RT use over time (P-trend=0.13). In multivariate analyses, increasing age at RT, site of BM (rib, shoulder, pelvis, and extremities), patients' area of residence (regional and remote), and treatment in public and metropolitan centres were associated with increased likelihood of SF-RT use. There was marked increase in ART use from 0.2% in 2012 to 24% in 2017 (11% intensity modulated RT, 13% SBRT) (P-trend<0.001). In multivariate analyses, younger age at RT, site of BM (rib and pelvis), higher socioeconomic status, and treatment in private and metropolitan centres were associated with increased likelihood of ART use.

Conclusion: SF-RT continues to be a clear minority of RT schedules employed in management of BM in PCa, and the adoption of SF-RT use should be encouraged in men with limited prognosis. There has been increasing use of ART, especially SBRT, for BM in PCa over time, and we expect this will continue to increase in the era of metastatic-directed treatment for PCa.
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http://dx.doi.org/10.1016/j.clgc.2021.07.007DOI Listing
July 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Bilateral salpingo-oophorectomy and breast cancer risk for BRCA1 and BRCA2 mutation carriers: Assessing the evidence.

Cancer Prev Res (Phila) 2021 Aug 4. Epub 2021 Aug 4.

Department of Medical Oncology, Peter MacCallum Cancer Centre

Without preventive interventions, women with germline pathogenic variants in BRCA1 or BRCA2 have high lifetime risks for breast cancer (BC) and tubo-ovarian cancer. The increased risk for BC 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 BRCA1 and BRCA2 mutation carriers, but whether it reduces BC risk is less clear. All studies of rrBSO and BC 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 BC risk, which is reflected by several international guidelines that recommend consideration of pre-menopausal rrBSO for BC 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 over-estimation 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 pre-menopausal rrBSO in reducing BC risk in BRCA1 or BRCA2 mutation carriers.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0141DOI Listing
August 2021

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Br J Cancer 2021 Aug 2. Epub 2021 Aug 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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http://dx.doi.org/10.1038/s41416-021-01432-8DOI Listing
August 2021

Inflammation-Related Marker Profiling of Dietary Patterns and All-cause Mortality in the Melbourne Collaborative Cohort Study.

J Nutr 2021 Jul 28. Epub 2021 Jul 28.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation.

Objectives: We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality.

Methods: Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y).

Results: The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-γ, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman ρ: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns.

Conclusions: Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E-DII, and the AHEI, especially kynurenines. Unfavorable marker scores, reflecting poorer-quality diets, were associated with increased mortality.
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http://dx.doi.org/10.1093/jn/nxab231DOI Listing
July 2021

Genomic Risk Prediction for Breast Cancer in Older Women.

Cancers (Basel) 2021 Jul 14;13(14). Epub 2021 Jul 14.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia.

Genomic risk prediction models for breast cancer (BC) have been predominantly developed with data from women aged 40-69 years. Prospective studies of older women aged ≥70 years have been limited. We assessed the effect of a 313-variant polygenic risk score (PRS) for BC in 6339 older women aged ≥70 years (mean age 75 years) enrolled into the ASPREE trial, a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. We evaluated incident BC diagnoses over a median follow-up time of 4.7 years. A multivariable Cox regression model including conventional BC risk factors was applied to prospective data, and re-evaluated after adding the PRS. We also assessed the association of rare pathogenic variants (PVs) in BC susceptibility genes (). The PRS, as a continuous variable, was an independent predictor of incident BC (hazard ratio (HR) per standard deviation (SD) = 1.4, 95% confidence interval (CI) 1.3-1.6) and hormone receptor (ER/PR)-positive disease (HR = 1.5 (CI 1.2-1.9)). Women in the top quintile of the PRS distribution had over two-fold higher risk of BC than women in the lowest quintile (HR = 2.2 (CI 1.2-3.9)). The concordance index of the model without the PRS was 0.62 (95% CI 0.56-0.68), which improved after addition of the PRS to 0.65 (95% CI 0.59-0.71). Among 41 (0.6%) carriers of PVs in BC susceptibility genes, we observed no incident BC diagnoses. Our study demonstrates that a PRS predicts incident BC risk in women aged 70 years and older, suggesting potential clinical utility extends to this older age group.
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http://dx.doi.org/10.3390/cancers13143533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305131PMC
July 2021

Factors Explaining Socio-Economic Inequalities in Survival from Colon Cancer: A Causal Mediation Analysis.

Cancer Epidemiol Biomarkers Prev 2021 Jul 16. Epub 2021 Jul 16.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: Socio-economic inequalities in colon cancer survival exist in high-income countries, but the reasons are unclear. We assessed the mediating effects of stage at diagnosis, comorbidities, and treatment (surgery and intravenous chemotherapy) on survival from colon cancer.

Methods: We identified 2,203 people aged 15 to 79 years with first primary colon cancer diagnosed in Victoria, Australia, between 2008 and 2011. Colon cancer cases were identified through the Victorian Cancer Registry (VCR), and clinical information was obtained from hospital records. Deaths till December 31, 2016 ( = 807), were identified from Victorian and national death registries. Socio-economic disadvantage was based on residential address at diagnosis. For stage III disease, we decomposed its total effect into direct and indirect effects using interventional mediation analysis.

Results: Socio-economic inequalities in colon cancer survival were not explained by stage and were greater for men than women. For men with stage III disease, there were 161 [95% confidence interval (CI), 67-256] additional deaths per 1,000 cases in the 5 years following diagnosis for the most disadvantaged compared with the least disadvantaged. The indirect effects through comorbidities and intravenous chemotherapy explained 6 (95% CI, -10-21) and 15 (95% CI, -14-44) per 1,000 of these additional deaths, respectively. Surgery did not explain the observed gap in survival.

Conclusions: Disadvantaged men have lower survival from stage III colon cancer that is only modestly explained by having comorbidities or not receiving chemotherapy after surgery.

Impact: Future studies should investigate the potential mediating role of factors occurring beyond the first year following diagnosis, such as compliance with surveillance for recurrence and supportive care services.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0222DOI Listing
July 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 Jul 13. Epub 2021 Jul 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
July 2021

Smoking, alcohol consumption, body fatness, and risk of myelodysplastic syndromes: A prospective study.

Leuk Res 2021 Apr 24;109:106593. Epub 2021 Apr 24.

Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria, 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, 3010, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, 3168, Australia.

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http://dx.doi.org/10.1016/j.leukres.2021.106593DOI Listing
April 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 Jul 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Bilateral Salpingo-Oophorectomy to Reduce Breast Cancer Risk in Women With Germline BRCA1 or BRCA2 Pathogenic Variants-Caution Needed.

JAMA Oncol 2021 Sep;7(9):1401

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1001/jamaoncol.2021.2037DOI Listing
September 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 06 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 07 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322933PMC
July 2021

Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging.

J Gerontol A Biol Sci Med Sci 2021 Jun 12. Epub 2021 Jun 12.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.

Background: Inflammation is a key feature of aging. We aimed to i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality, ii) develop a signature of 'inflammaging'.

Methods: Thirty-four blood markers relating to inflammation, B vitamin status and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age=59 years) and follow-up (median age=70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with two marker scores calculated across all markers associated with age and mortality, respectively.

Results: The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, IL-6, TNF-α, several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5´-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, CRP, quinolinic acid, PAr index, and KTR. The inflammaging signature included ten markers and was strongly associated of mortality (HR per SD=1.40, 95%CI:1.24-1.57, P=2x10 -8), similar to scores based on all age-associated (HR=1.38, 95%CI:1.23-1.55, P=4x10 -8) and mortality-associated markers (HR=1.43, 95%CI:1.28-1.60, P=1x10 -10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study.

Conclusion: Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on ten markers was strongly associated with mortality.
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http://dx.doi.org/10.1093/gerona/glab163DOI Listing
June 2021

DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer.

Cancers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia.

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups ( = 3.7 × 10) and young people without CRC ( = 5.8 × 10). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.
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http://dx.doi.org/10.3390/cancers13112589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199056PMC
May 2021

Differences in treatment choices for localised prostate cancer diagnosed in private and public health services.

Med J Aust 2021 06 11;214(10):486-486.e1. Epub 2021 May 11.

Cabrini Health, Melbourne, VIC.

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http://dx.doi.org/10.5694/mja2.51073DOI Listing
June 2021

Prospective Evaluation of the Addition of Polygenic Risk Scores to Breast Cancer Risk Models.

JNCI Cancer Spectr 2021 Jun 2;5(3):pkab021. Epub 2021 Mar 2.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm and the International Breast Cancer Intervention Study breast cancer risk models are used to provide advice on screening intervals and chemoprevention. We evaluated the performance of these models, which now incorporate polygenic risk scores (PRSs), using a prospective cohort study.

Methods: We used a case-cohort design, involving women in the Melbourne Collaborative Cohort Study aged 50-75 years when surveyed in 2003-2007, of whom 408 had a first primary breast cancer diagnosed within 10 years (cases), and 2783 were from the subcohort. Ten-year risks were calculated based on lifestyle factors, family history data, and a 313-variant PRS. Discrimination was assessed using a C-statistic compared with 0.50 and calibration using the ratio of expected to observed number of cases (E/O).

Results: When the PRS was added to models with lifestyle factors and family history, the C-statistic (95% confidence interval [CI]) increased from 0.57 (0.54 to 0.60) to 0.62 (0.60 to 0.65) using IBIS and from 0.56 (0.53 to 0.59) to 0.62 (0.59 to 0.64) using BOADICEA. IBIS underpredicted risk (E/O = 0.62, 95% CI = 0.48 to 0.80) for women in the lowest risk category (<1.7%) and overpredicted risk (E/O = 1.40, 95% CI = 1.18 to 1.67) in the highest risk category (≥5%), using the Hosmer-Lemeshow test for calibration in quantiles of risk and a 2-sided value less than.001. BOADICEA underpredicted risk (E/O = 0.82, 95% CI = 0.67 to 0.99) in the second highest risk category (3.4%-5%); the Hosmer-Lemeshow test and a 2-sided valuewas equal to .02.

Conclusions: Although the inclusion of a 313 genetic variant PRS doubles discriminatory accuracy (relative to reference 0.50), models with and without this PRS have relatively modest discrimination and might require recalibration before their clinical and wider use are promoted.
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http://dx.doi.org/10.1093/jncics/pkab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099999PMC
June 2021

Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study.

Cancer Epidemiol Biomarkers Prev 2021 Jul 10;30(7):1349-1358. Epub 2021 May 10.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival.

Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components.

Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years; = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location.

Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival.

Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254760PMC
July 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 08;114(2):450-461

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.

Objective: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.

Method: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.

Results: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326053PMC
August 2021

Factors Explaining Socio-Economic Inequalities in Cancer Survival: A Systematic Review.

Cancer Control 2021 Jan-Dec;28:10732748211011956

Cancer Epidemiology Division, 56367Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: There is strong and well-documented evidence that socio-economic inequality in cancer survival exists within and between countries, but the underlying causes of these differences are not well understood.

Methods: We systematically searched the Ovid Medline, EMBASE, and CINAHL databases up to 31 May 2020. Observational studies exploring pathways by which socio-economic position (SEP) might causally influence cancer survival were included.

Results: We found 74 eligible articles published between 2005 and 2020. Cancer stage, other tumor characteristics, health-related lifestyle behaviors, co-morbidities and treatment were reported as key contributing factors, although the potential mediating effect of these factors varied across cancer sites. For common cancers such as breast and prostate cancer, stage of disease was generally cited as the primary explanatory factor, while co-morbid conditions and treatment were also reported to contribute to lower survival for more disadvantaged cases. In contrast, for colorectal cancer, most studies found that stage did not explain the observed differences in survival by SEP. For lung cancer, inequalities in survival appear to be partly explained by receipt of treatment and co-morbidities.

Conclusions: Most studies compared regression models with and without adjusting for potential mediators; this method has several limitations in the presence of multiple mediators that could result in biased estimates of mediating effects and invalid conclusions. It is therefore essential that future studies apply modern methods of causal mediation analysis to accurately estimate the contribution of potential explanatory factors for these inequalities, which may translate into effective interventions to improve survival for disadvantaged cancer patients.
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http://dx.doi.org/10.1177/10732748211011956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204531PMC
April 2021

Diet scores and prediction of general and abdominal obesity in the Melbourne collaborative cohort study.

Public Health Nutr 2021 Apr 20:1-12. Epub 2021 Apr 20.

Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.

Objective: To ascertain which of the Alternative Healthy Eating Index (AHEI) 2010, Dietary Inflammatory Index (DII®) and Mediterranean Diet Score (MDS) best predicted BMI and waist-to-hip circumference ratio (WHR).

Design: Body size was measured at baseline (1990-1994) and in 2003-2007. Diet was assessed at baseline using a FFQ, along with age, sex, socio-economic status, smoking, alcohol drinking, physical activity and country of birth. Regression coefficients and 95 % CI for the association of baseline dietary scores with follow-up BMI and WHR were generated using multivariable linear regression, adjusting for baseline body size, confounders and energy intake.

Setting: Population-based cohort in Melbourne, Australia.

Participants: Included were data from 11 030 men and 16 774 women aged 40-69 years at baseline.

Results: Median (IQR) follow-up was 11·6 (10·7-12·8) years. BMI and WHR at follow-up were associated with baseline DII® (Q5 v. Q1 (BMI 0·41, 95 % CI 0·21, 0·61) and WHR 0·009, 95 % CI 0·006, 0·013)) and AHEI (Q5 v. Q1 (BMI -0·51, 95 % CI -0·68, -0·35) and WHR -0·011, 95 % CI -0·013, -0·008)). WHR, but not BMI, at follow-up was associated with baseline MDS (Group 3 most Mediterranean v. G1 (BMI -0·05, 95 % CI -0·23, 0·13) and WHR -0·004, 95 % CI -0·007, -0·001)). Based on Akaike's Information Criterion and Bayesian Information Criterion statistics, AHEI was a stronger predictor of body size than the other diet scores.

Conclusions: Poor quality or pro-inflammatory diets predicted overall and central obesity. The AHEI may provide the best way to assess the obesogenic potential of diet.
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http://dx.doi.org/10.1017/S1368980021001713DOI Listing
April 2021

Prediagnosis alcohol intake and metachronous cancer risk in cancer survivors: A prospective cohort study.

Int J Cancer 2021 Apr 19. Epub 2021 Apr 19.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Alcohol consumption is a known cause of cancer, but its role in the etiology of second primary (metachronous) cancer is uncertain. Associations between alcohol intake up until study enrollment (prediagnosis) and risk of metachronous cancer were estimated using 9435 participants in the Melbourne Collaborative Cohort Study who were diagnosed with their first invasive cancer after enrollment (1990-1994). Follow-up was from date of first invasive cancer until diagnosis of metachronous cancer, death or censor date (February 2018), whichever came first. Alcohol intake for 10-year periods from age 20 until decade encompassing baseline using recalled beverage-specific frequency and quantity was used to calculate baseline and lifetime intakes, and group-based intake trajectories. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. After a mean follow-up of 7 years, 1512 metachronous cancers were identified. A 10 g/d increment in prediagnosis lifetime alcohol intake (HR = 1.03, 95% CI = 1.00-1.06; P = .02) and an intake of ≥60 g/d (HR = 1.32, 95% CI = 1.01-1.73) were associated with increased metachronous cancer risk. We observed positive associations (per 10 g/d increment) for metachronous colorectal (HR = 1.07, 95% CI = 1.00-1.14), upper aero-digestive tract (UADT) (HR = 1.16, 95% CI = 1.00-1.34) and kidney cancer (HR = 1.24, 95% CI = 1.10-1.39). Although these findings were partly explained by effects of smoking, the association for kidney cancer remained unchanged when current smokers or obese individuals were excluded. Alcohol intake trajectories over the life course confirmed associations with metachronous cancer risk. Prediagnosis long-term alcohol intake, and particularly heavy drinking, may increase the risk of metachronous cancer, particularly of the colorectum, UADT and kidney.
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http://dx.doi.org/10.1002/ijc.33603DOI Listing
April 2021

Predicting Australian Adults at High Risk of Cardiovascular Disease Mortality Using Standard Risk Factors and Machine Learning.

Int J Environ Res Public Health 2021 03 19;18(6). Epub 2021 Mar 19.

Flinders Digital Health Research Centre, College of Nursing & Health Sciences, Flinders University, Adelaide SA 5001, Australia.

Effective cardiovascular disease (CVD) prevention relies on timely identification and intervention for individuals at risk. Conventional formula-based techniques have been demonstrated to over- or under-predict the risk of CVD in the Australian population. This study assessed the ability of machine learning models to predict CVD mortality risk in the Australian population and compare performance with the well-established Framingham model. Data is drawn from three Australian cohort studies: the North West Adelaide Health Study (NWAHS), the Australian Diabetes, Obesity, and Lifestyle study, and the Melbourne Collaborative Cohort Study (MCCS). Four machine learning models for predicting 15-year CVD mortality risk were developed and compared to the 2008 Framingham model. Machine learning models performed significantly better compared to the Framingham model when applied to the three Australian cohorts. Machine learning based models improved prediction by 2.7% to 5.2% across three Australian cohorts. In an aggregated cohort, machine learning models improved prediction by up to 5.1% (area-under-curve (AUC) 0.852, 95% CI 0.837-0.867). Net reclassification improvement (NRI) was up to 26% with machine learning models. Machine learning based models also showed improved performance when stratified by sex and diabetes status. Results suggest a potential for improving CVD risk prediction in the Australian population using machine learning models.
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http://dx.doi.org/10.3390/ijerph18063187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003399PMC
March 2021

Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC 3168, Australia.

While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant ( < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in (5.8 (2.7-12.4)), (5.5 (1.8-16.6)), and (3.8 (1.6-9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.
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http://dx.doi.org/10.3390/cancers13071495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036662PMC
March 2021
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