Melbourne School of Population and Global Health - Research Publications

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    Adherence to 2018 WCRF/AICR Cancer Prevention Recommendations and Risk of Cancer: The Melbourne Collaborative Cohort Study.
    Peng, Y ; Bassett, JK ; Hodge, AM ; Melaku, YA ; Afshar, N ; Hopper, JL ; MacInnis, RJ ; Lynch, BM ; Smith-Warner, SA ; Giles, GG ; Milne, RL ; Jayasekara, H (American Association for Cancer Research (AACR), 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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    Intratumoral presence of the genotoxic gut bacteria pks+ E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer
    Joo, JE ; Chu, YL ; Georgeson, P ; Walker, R ; Mahmood, K ; Clendenning, M ; Meyers, AL ; Como, J ; Joseland, S ; Preston, SG ; Diepenhorst, N ; Toner, J ; Ingle, DJ ; Sherry, NL ; Metz, A ; Lynch, BM ; Milne, RL ; Southey, MC ; Hopper, JL ; Win, AK ; Macrae, FA ; Winship, IM ; Rosty, C ; Jenkins, MA ; Buchanan, DD (Springer Nature, 2024)
    Background: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+ Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum). Methods: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. Results: Pks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01). Conclusion: Intratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.
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    Modifiable lifestyle risk factors and survival after diagnosis with multiple myeloma
    Cheah, S ; Bassett, JK ; Bruinsma, FJ ; Hopper, J ; Jayasekara, H ; Joshua, D ; Macinnis, RJ ; Prince, HM ; Southey, MC ; Vajdic, CM ; van Leeuwen, MT ; Doo, NW ; Harrison, SJ ; English, DR ; Giles, GG ; Milne, RL (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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    Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium
    Kast, KM ; John, EL ; Hopper, J ; Andrieu, N ; Nogues, C ; Mouret-Fourme, E ; Lasset, C ; Fricker, J-P ; Berthet, P ; Mari, V ; Salle, LK ; Schmidt, M ; Ausems, MGEM ; Garcia, EBG ; van de Beek, IR ; Wevers, M ; Evans, DG ; Tischkowitz, M ; Lalloo, F ; Cook, J ; Izatt, L ; Tripathi, V ; Snape, K ; Musgrave, H ; Sharif, S ; Murray, JV ; Colonna, SV ; Andrulis, IL ; Daly, MB ; Southey, MC ; de la Hoya, M ; Osorio, A ; Foretova, L ; Berkova, D ; Gerdes, A-M ; Olah, E ; Jakubowska, A ; Singer, CF ; Tan, Y ; Augustinsson, A ; Rantala, J ; Simard, J ; Schmutzler, RK ; Milne, RL ; Phillips, K-A ; Terry, MB ; Goldgar, D ; van Leeuwen, FE ; Mooij, TM ; Antoniou, AC ; Easton, DF ; Rookus, MA ; Engel, C (BMC, 2023-06-20)
    INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
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    A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2
    Zanti, M ; O'Mahony, DG ; Parsons, MT ; Li, H ; Dennis, J ; Aittomäkkiki, K ; Andrulis, IL ; Anton-Culver, H ; Aronson, KJ ; Augustinsson, A ; Becher, H ; Bojesen, SE ; Bolla, MK ; Brenner, H ; Brown, MA ; Buys, SS ; Canzian, F ; Caputo, SM ; Castelao, JE ; Chang-Claude, J ; Czene, K ; Daly, MB ; De Nicolo, A ; Devilee, P ; Dörk, T ; Dunning, AM ; Dwek, M ; Eccles, DM ; Engel, C ; Gareth Evans, D ; Fasching, PA ; Gago-Dominguez, M ; García-Closas, M ; García-Sáenz, JA ; Gentry-Maharaj, A ; Geurts-Giele, WRR ; Giles, GG ; Glendon, G ; Goldberg, MS ; Gómez Garcia, EB ; Göendert, M ; Guénel, P ; Hahnen, E ; Haiman, CA ; Hall, P ; Hamann, U ; Harkness, EF ; Hogervorst, FBL ; Hollestelle, A ; Hoppe, R ; Hopper, JL ; Houdayer, C ; Houlston, RS ; Howell, A ; Jakimovska, M ; Jakubowska, A ; Jernström, H ; John, EM ; Kaaks, R ; Kitahara, CM ; Koutros, S ; Kraft, P ; Kristensen, VN ; Lacey, JV ; Lambrechts, D ; Léoné, M ; Lindblom, A ; Lubiski, J ; Lush, M ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martinez, ME ; Menon, U ; Milne, RL ; Monteiro, AN ; Murphy, RA ; Neuhausen, SL ; Nevanlinna, H ; Newman, WG ; Offit, K ; Park, SK ; James, P ; Peterlongo, P ; Peto, J ; Plaseska-Karanfilska, D ; Punie, K ; Radice, P ; Rashid, MU ; Rennert, G ; Romero, A ; Rosenberg, EH ; Saloustros, E ; Sandler, DP ; Schmidt, MK ; Schmutzler, RK ; Shu, XO ; Simard, J ; Southey, MC ; Cutting, G (Hindawi Limited, 2023-01-01)
    A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.
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    Pre-diagnostic cigarette smoking and risk of second primary cancer: The Melbourne Collaborative Cohort Study
    Phua, ZJ ; MacInnis, RJ ; Hodge, AM ; Lynch, BM ; Hopper, JL ; Smith-Warner, SA ; Giles, GG ; Milne, RL ; Jayasekara, H (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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    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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    Methylation scores for smoking, alcohol consumption and body mass index and risk of seven types of cancer
    Dugue, P-A ; Yu, C ; Hodge, AMM ; Wong, EM ; Joo, JEE ; Jung, C-H ; Schmidt, D ; Makalic, E ; Buchanan, DDD ; Severi, G ; English, DRR ; Hopper, JLL ; Milne, RLL ; Giles, GGG ; Southey, MCC (WILEY, 2023-08-01)
    Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values. Rate ratios (RR) and 95% confidence intervals for association with cancer risk were estimated using conditional logistic regression and expressed per SD increase of the MS, with and without adjustment for health-related confounders. The contribution of MS to discriminate cases from controls was evaluated using the area under the curve (AUC). After confounder adjustment, we observed: large associations (RR = 1.5-1.7) with lung cancer risk for smoking MS; moderate associations (RR = 1.2-1.3) with urothelial cancer risk for smoking MS and with mature B-cell neoplasm risk for BMI and alcohol MS; moderate to small associations (RR = 1.1-1.2) for BMI and alcohol MS with several cancer types and cancer overall. Generally small AUC increases were observed after inclusion of several MS in the same model (colorectal, gastric, kidney, urothelial cancers: +3%; lung cancer: +7%; B-cell neoplasms: +8%). Methylation scores for smoking, BMI and alcohol consumption show independent associations with cancer risk, and may provide some improvements in risk prediction.