Melbourne School of Population and Global Health - Research Publications

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    Association of contralateral breast cancer risk with mammographic density defined at higher-than-conventional intensity thresholds
    Watt, GP ; Knight, JA ; Nguyen, TL ; Reiner, AS ; Malone, KE ; John, EM ; Lynch, CF ; Brooks, JD ; Woods, M ; Liang, X ; Bernstein, L ; Pike, MC ; Hopper, JL ; Bernstein, JL (WILEY, 2022-10-15)
    Mammographic dense area (MDA) is an established predictor of future breast cancer risk. Recent studies have found that risk prediction might be improved by redefining MDA in effect at higher-than-conventional intensity thresholds. We assessed whether such higher-intensity MDA measures gave stronger prediction of subsequent contralateral breast cancer (CBC) risk using the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based CBC case-control study of ≥1 year survivors of unilateral breast cancer diagnosed between 1990 and 2008. Three measures of MDA for the unaffected contralateral breast were made at the conventional intensity threshold ("Cumulus") and at two sequentially higher-intensity thresholds ("Altocumulus" and "Cirrocumulus") using the CUMULUS software and mammograms taken up to 3 years prior to the first breast cancer diagnosis. The measures were fitted separately and together in multivariable-adjusted logistic regression models of CBC (252 CBC cases and 271 unilateral breast cancer controls). The strongest association with CBC was MDA defined using the highest intensity threshold, Cirrocumulus (odds ratio per adjusted SD [OPERA] 1.40, 95% CI 1.13-1.73); and the weakest association was MDA defined at the conventional threshold, Cumulus (1.32, 95% CI 1.05-1.66). In a model fitting the three measures together, the association of CBC with Cirrocumulus was unchanged (1.40, 95% CI 0.97-2.05), and the lower brightness measures did not contribute to the CBC model fit. These results suggest that MDA defined at a high-intensity threshold is a better predictor of CBC risk and has the potential to improve CBC risk stratification beyond conventional MDA measures.
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    Women's thoughts on receiving and sharing genetic information: Considerations for genetic counseling
    Pfledderer, CD ; Gren, LH ; Frost, CJ ; Andrulis, IL ; Chung, WK ; Genkinger, J ; Glendon, G ; Hopper, JL ; John, EM ; Southey, M ; Terry, MB ; Daly, MB (WILEY, 2022-12)
    Indications for genetic testing for inherited cancer syndromes are expanding both in the academic and the community setting. However, only a fraction of individuals who are candidates for testing pursue this option. Therefore, it is important to understand those factors that impact the uptake of genetic testing in individuals affected and unaffected with cancer. A successful translation of genomic risk stratification into clinical care will require that providers of this information are aware of the attitudes, perceived risks and benefits, and concerns of individuals who will be considering testing. The purpose of this study was to assess beliefs, attitudes and preferences for genetic risk information, by personal characteristics of women affected and unaffected by breast cancer enrolled in the Breast Cancer Family Registry Cohort. Data for this analysis came from eight survey questions, which asked participants (N = 9,048, 100% female) about their opinions regarding genetic information. Women reported that conveying the accuracy of the test was important and were interested in information related to personal level of risk, finding out about diseases that could be treated, and information that could be helpful to their families. Young women were most interested in how their own health needs might be impacted by genetic test results, while older women were more interested in how genetic information would benefit other members of the family. Interest in how the genetic test was performed was highest among Asian and Hispanic women. Women affected with breast cancer were more likely to report feeling sad about possibly passing down a breast cancer gene, while unaffected women were more uncertain about their future risk of cancer. The variety of informational needs identified has implications for how genetic counselors can tailor communication to individuals considering genetic testing.
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    PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ∼ 200,000 patients (vol 24, 69, 2022)
    Giardiello, D ; Hooning, MJ ; Hauptmann, M ; Keeman, R ; Heemskerk-Gerritsen, BAM ; Becher, H ; Blomqvist, C ; Bojesen, SE ; Bolla, MK ; Camp, NJ ; Czene, K ; Devilee, P ; Eccles, DM ; Fasching, PA ; Figueroa, JD ; Flyger, H ; Garcia-Closas, M ; Haiman, CA ; Hamann, U ; Hopper, JL ; Jakubowska, A ; Leeuwen, FE ; Lindblom, A ; Lubinski, J ; Margolin, S ; Martinez, ME ; Nevanlinna, H ; Nevelsteen, I ; Pelders, S ; Pharoah, PDP ; Siesling, S ; Southey, MC ; van der Hout, AH ; van Hest, LP ; Chang-Claude, J ; Hall, P ; Easton, DF ; Steyerberg, EW ; Schmidt, MK (BMC, 2022-11-22)
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    PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ∼200,000 patients
    Giardiello, D ; Hooning, MJ ; Hauptmann, M ; Keeman, R ; Heemskerk-Gerritsen, BAM ; Becher, H ; Blomqvist, C ; Bojesen, SE ; Bolla, MK ; Camp, NJ ; Czene, K ; Devilee, P ; Eccles, DM ; Fasching, PA ; Figueroa, JD ; Flyger, H ; Garcia-Closas, M ; Haiman, CA ; Hamann, U ; Hopper, JL ; Jakubowska, A ; Leeuwen, FE ; Lindblom, A ; Lubinski, J ; Margolin, S ; Martinez, ME ; Nevanlinna, H ; Nevelsteen, I ; Pelders, S ; Pharoah, PDP ; Siesling, S ; Southey, MC ; van der Hout, AH ; van Hest, LP ; Chang-Claude, J ; Hall, P ; Easton, DF ; Steyerberg, EW ; Schmidt, MK (BMC, 2022-10-21)
    BACKGROUND: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. METHODS: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. RESULTS: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56-0.74) versus 0.63 (95%PI 0.54-0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34-2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.
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    Polygenic risk scores for cardiovascular diseases and type 2 diabetes
    Wong, CK ; Makalic, E ; Dite, GS ; Whiting, L ; Murphy, NM ; Hopper, JL ; Allman, R ; Colombo, GI (PUBLIC LIBRARY SCIENCE, 2022-12-02)
    Polygenic risk scores (PRSs) are a promising approach to accurately predict an individual's risk of developing disease. The area under the receiver operating characteristic curve (AUC) of PRSs in their population are often only reported for models that are adjusted for age and sex, which are known risk factors for the disease of interest and confound the association between the PRS and the disease. This makes comparison of PRS between studies difficult because the genetic effects cannot be disentangled from effects of age and sex (which have a high AUC without the PRS). In this study, we used data from the UK Biobank and applied the stacked clumping and thresholding method and a variation called maximum clumping and thresholding method to develop PRSs to predict coronary artery disease, hypertension, atrial fibrillation, stroke and type 2 diabetes. We created case-control training datasets in which age and sex were controlled by design. We also excluded prevalent cases to prevent biased estimation of disease risks. The maximum clumping and thresholding PRSs required many fewer single-nucleotide polymorphisms to achieve almost the same discriminatory ability as the stacked clumping and thresholding PRSs. Using the testing datasets, the AUCs for the maximum clumping and thresholding PRSs were 0.599 (95% confidence interval [CI]: 0.585, 0.613) for atrial fibrillation, 0.572 (95% CI: 0.560, 0.584) for coronary artery disease, 0.585 (95% CI: 0.564, 0.605) for type 2 diabetes, 0.559 (95% CI: 0.550, 0.569) for hypertension and 0.514 (95% CI: 0.494, 0.535) for stroke. By developing a PRS using a dataset in which age and sex are controlled by design, we have obtained true estimates of the discriminatory ability of the PRSs alone rather than estimates that include the effects of age and sex.
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    Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study
    Dixon-Suen, SC ; Lewis, SJ ; Martin, RM ; English, DR ; Boyle, T ; Giles, GG ; Michailidou, K ; Bolla, MK ; Wang, Q ; Dennis, J ; Lush, M ; Ahearn, TU ; Ambrosone, CB ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Auvinen, P ; Beane Freeman, LE ; Becher, H ; Beckmann, MW ; Behrens, S ; Bermisheva, M ; Blomqvist, C ; Bogdanova, N ; Bojesen, SE ; Bonanni, B ; Brenner, H ; Bruening, T ; Buys, SS ; Camp, NJ ; Campa, D ; Canzian, F ; Castelao, JE ; Cessna, MH ; Chang-Claude, J ; Chanock, SJ ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Doerk, T ; Dwek, M ; Eccles, DM ; Eliassen, AH ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Fletcher, O ; Flyger, H ; Fritschi, L ; Gabrielson, M ; Gago-Dominguez, M ; Garcia-Closas, M ; Garcia-Saenz, JA ; Goldberg, MS ; Guenel, P ; Guendert, M ; Hahnen, E ; Haiman, CA ; Haeberle, L ; Hakansson, N ; Hall, P ; Hamann, U ; Hart, SN ; Harvie, M ; Hillemanns, P ; Hollestelle, A ; Hooning, MJ ; Hoppe, R ; Hopper, J ; Howell, A ; Hunter, DJ ; Jakubowska, A ; Janni, W ; John, EM ; Jung, A ; Kaaks, R ; Keeman, R ; Kitahara, CM ; Koutros, S ; Kraft, P ; Kristensen, VN ; Kubelka-Sabit, K ; Kurian, AW ; Lacey, J ; Lambrechts, D ; Le Marchand, L ; Lindblom, A ; Loibl, S ; Lubinski, J ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Martinez, ME ; Mavroudis, D ; Menon, U ; Mulligan, AM ; Murphy, RA ; Nevanlinna, H ; Nevelsteen, I ; Newman, WG ; Offit, K ; Olshan, AF ; Olsson, H ; Orr, N ; Patel, A ; Peto, J ; Plaseska-Karanfilska, D ; Presneau, N ; Rack, B ; Radice, P ; Rees-Punia, E ; Rennert, G ; Rennert, HS ; Romero, A ; Saloustros, E ; Sandler, DP ; Schmidt, MK ; Schmutzler, RK ; Schwentner, L ; Scott, C ; Shah, M ; Shu, X-O ; Simard, J ; Southey, MC ; Stone, J ; Surowy, H ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Terry, MB ; Tollenaar, RAEM ; Troester, MA ; Truong, T ; Untch, M ; Vachon, CM ; Joseph, V ; Wappenschmidt, B ; Weinberg, CR ; Wolk, A ; Yannoukakos, D ; Zheng, W ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Milne, RL ; Lynch, BM (BMJ PUBLISHING GROUP, 2022-10)
    OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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    Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies
    Jung, AY ; Ahearn, TU ; Behrens, S ; Middha, P ; Bolla, MK ; Wang, Q ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Freeman, LEB ; Becher, H ; Brenner, H ; Canzian, F ; Carey, LA ; Consortium, C ; Czene, K ; Eliassen, AH ; Eriksson, M ; Evans, DG ; Figueroa, JD ; Fritschi, L ; Gabrielson, M ; Giles, GG ; Guenel, P ; Hadjisavvas, A ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Hoppe, R ; Hopper, JL ; Howell, A ; Hunter, DJ ; Huesing, A ; Kaaks, R ; Kosma, V-M ; Koutros, S ; Kraft, P ; Lacey, J ; Le Marchand, L ; Lissowska, J ; Loizidou, MA ; Mannermaa, A ; Maurer, T ; Murphy, RA ; Olshan, AF ; Olsson, H ; Patel, A ; Perou, CM ; Rennert, G ; Shibli, R ; Shu, X-O ; Southey, MC ; Stone, J ; Tamimi, RM ; Teras, LR ; Troester, MA ; Truong, T ; Vachon, CM ; Wang, SS ; Wolk, A ; Wu, AH ; Yang, XR ; Zheng, W ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Milne, RL ; Chatterjee, N ; Schmidt, MK ; Garcia-Closas, M ; Chang-Claude, J (OXFORD UNIV PRESS INC, 2022-12)
    BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSIONS: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.
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    Does genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?
    Yu, C ; Hodge, AM ; Wong, EM ; Joo, JE ; Makalic, E ; Schmidt, DF ; Buchanan, DD ; Severi, G ; Hopper, JL ; English, DR ; Giles, GG ; Milne, RL ; Southey, MC ; Dugue, P-A (TAYLOR & FRANCIS INC, 2022-12-02)
    Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N = 7,431) and validation (N = 4,307) samples. Using paired genetic-methylation data (N = 4,307), gene-environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAge and GrimAge. In the validation sample, PGS explained ~1.4% (P = 1 × 10-14), ~0.6% (P = 2 × 10-7), and ~8.7% (P = 7 × 10-87) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (P < 0.05) were found at 61, 14, and 7 CpGs for smoking, alcohol consumption, and BMI, respectively. There was strong evidence that all lifestyle-related phenotypes were positively associated with PhenoAge and GrimAge, except for alcohol consumption with PhenoAge. There was weak evidence that the association of smoking with GrimAge was attenuated in participants genetically predisposed to smoking (interaction term: -0.022, standard error [SE] = 0.012, P = 0.058) and that the association of alcohol consumption with PhenoAge was attenuated in those genetically predisposed to drink alcohol (interaction term: -0.030, SE = 0.015, P = 0.041). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify the association between observed lifestyle behaviour and blood DNA methylation. Potential associations were observed for epigenetic ageing measures, which should be replicated in additional studies.
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    What if the age at which a woman started regular mammographic screening depended on her risk, not age?
    Hopper, JL ; Nguyen, TL ; Li, S (WILEY, 2022-12-15)
    Lay summary Durham and colleagues found evidence that mammographic screening for breast cancer could start earlier if a woman had a first‐degree relative with breast cancer, no matter how old the relative was at diagnosis. The difference between the age at diagnosis of the relative and the age of starting screening was not a fixed number such as 10 years: it actually increased with the age at diagnosis of the relative. Therefore, this is not just an issue for young women with a relative diagnosed with breast cancer at a young age, and it has wide implications for mammographic screening worldwide.
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    Body Mass Index, sex, non-steroidal anti-inflammatory drug medications, smoking and alcohol are differentially associated with World Health Organisation criteria and colorectal cancer risk in people with Serrated Polyposis Syndrome: an Australian case-control study
    Anthony, E ; Reece, JC ; Milanzi, E ; Joo, JE ; Joseland, S ; Clendenning, M ; Whelan, A ; Parry, S ; Arnold, J ; Vijay, V ; Atkinson, N ; Hopper, JL ; Win, AK ; Jenkins, MA ; Macrae, FA ; Winship, IM ; Rosty, C ; Buchanan, DD (BMC, 2022-11-26)
    OBJECTIVE: The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO)2010 clinical criteria and by colorectal cancer (CRC). METHOD: A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS. RESULTS: Female biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77-7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04-1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75-0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64-0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23-0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18-0.83) was associated with WHO criterion III only. Smoking 1-5 cigarettes daily (OR = 2.35; 95%CI = 1.09-5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78-0.99), and increased height (OR = 1.09; 95% = 1.05-1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67-0.98) was associated with a reduced likelihood of CRC in SPS. CONCLUSION: We identified novel risk and potential protective factors associated with SPS, some specific for certain WHO2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS.