Melbourne School of Population and Global Health - Research Publications

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    Linking Physical Activity to Breast Cancer: Text Mining Results and a Protocol for Systematically Reviewing Three Potential Mechanistic Pathways
    Lynch, BM ; Milne, RL ; English, DR ; Brown, KA ; Drummond, AE ; Swain, CT ; van Roekel, EH ; Moore, MM ; Gaunt, TR ; Martin, RM ; Lewis, SJ (AMER ASSOC CANCER RESEARCH, 2022-01)
    Epidemiologic research suggests that physical activity is associated with a reduced risk of breast cancer, but the causal nature of this link is not clear. Investigating mechanistic pathways can provide evidence of biological plausibility and improve causal inference. This project will examine three putative pathways (sex steroid hormones, insulin signaling, and inflammation) in a series of two-stage systematic reviews. Stage 1 used Text Mining for Mechanism Prioritisation (TeMMPo) to identify and prioritize relevant biological intermediates. Stage 2 will systematically review the findings from studies of (i) physical activity and intermediates and (ii) intermediates and breast cancer. Ovid MEDLINE, EMBASE, and SPORTDiscus will be searched using a combination of subject headings and free-text terms. Human intervention and prospective, observational studies will be eligible for inclusion. Meta-analysis will be performed where possible. Risk of bias will be assessed using the Cochrane Collaboration tool, or the ROBINS-I or ROBINS-E tool, depending on study type. Strength of evidence will be assessed using the GRADE system. In addition to synthesizing the mechanistic evidence that links physical activity with breast cancer risk, this project may also identify priority areas for future research and help inform the design and implementation of physical activity interventions.See related reviews by Swain et al., p. 16 and Drummond et al., p. 28.
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    Socio-economic and ethnocultural influences on geographical disparities in breast cancer screening participation in Victoria, Australia.
    Stuart, GW ; Chamberlain, JA ; Milne, RL (Frontiers Media SA, 2022)
    OBJECTIVE: To examine the socio-economic and ethnocultural characteristics of geographical areas that may influence variation in breast cancer screening participation. METHODS: In a cross-sectional analysis breast cancer screening participation for statistical areas in Victoria, Australia (2015-2017) was linked with data from the 2016 Australian Census. We selected four commonly used area-level measures of socio-economic status from the Australian Census (i) income (ii) educational level (iii) occupational status and (iv) employment profile. To assess the ethnocultural characteristics of statistical areas we used the Census measures (i) country of birth (ii) language spoken at home (iii) fluency in English (iv) religion and (v) the proportion of immigrants in an area, together with their recency of migration. RESULTS: All the selected measures were related to screening participation. There was a high degree of association both within and between socio-economic and ethnocultural characteristics of areas as they relate to screening. Ethnocultural characteristics alone accounted for most of the explained geographical disparity in screening participation. CONCLUSIONS: Geographical disparities in breast cancer screening participation may be due to ethnocultural factors that are confounded with socio-economic factors.
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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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    Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
    Tian, Y ; Kim, AE ; Bien, SA ; Lin, Y ; Qu, C ; Harrison, TA ; Carreras-Torres, R ; Diez-Obrero, V ; Dimou, N ; Drew, DA ; Hidaka, A ; Huyghe, JR ; Jordahl, KM ; Morrison, J ; Murphy, N ; Obon-Santacana, M ; Ulrich, CM ; Ose, J ; Peoples, AR ; Ruiz-Narvaez, EA ; Shcherbina, A ; Stern, MC ; Su, Y-R ; van Duijnhoven, FJB ; Arndt, V ; Baurley, JW ; Berndt, S ; Bishop, DT ; Brenner, H ; Buchanan, DD ; Chan, AT ; Figueiredo, JC ; Gallinger, S ; Gruber, SB ; Harlid, S ; Hoffmeister, M ; Jenkins, MA ; Joshi, AD ; Keku, TO ; Larsson, SC ; Le Marchand, L ; Li, L ; Giles, GG ; Milne, RL ; Nan, H ; Nassir, R ; Ogino, S ; Budiarto, A ; Platz, EA ; Potter, JD ; Prentice, RL ; Rennert, G ; Sakoda, LC ; Schoen, RE ; Slattery, ML ; Thibodeau, SN ; Van Guelpen, B ; Visvanathan, K ; White, E ; Wolk, A ; Woods, MO ; Wu, AH ; Campbell, PT ; Casey, G ; Conti, D ; Gunter, MJ ; Kundaje, A ; Lewinger, JP ; Moreno, V ; Newcomb, PA ; Pardamean, B ; Thomas, DC ; Tsilidis, KK ; Peters, U ; Gauderman, WJ ; Hsu, L ; Chang-Claude, J (OXFORD UNIV PRESS INC, 2022-08-08)
    BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
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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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    Genetic variants associated with circulating C-reactive protein levels and colorectal cancer survival: Sex-specific and lifestyle factors specific associations
    Huang, Y ; Hua, X ; Labadie, JD ; Harrison, TA ; Dai, JY ; Lindstrom, S ; Lin, Y ; Berndt, S ; Buchanan, DD ; Campbell, PT ; Casey, G ; Gallinger, SJ ; Gunter, MJ ; Hoffmeister, M ; Jenkins, MA ; Sakoda, LC ; Schoen, RE ; Diergaarde, B ; Slattery, ML ; White, E ; Giles, G ; Brenner, H ; Chang-Claude, J ; Joshi, A ; Ma, W ; Pai, RK ; Chan, AT ; Peters, U ; Newcomb, PA (WILEY, 2022-05-01)
    Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.
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    Alcohol intake trajectories during the life course and risk of alcohol-related cancer: A prospective cohort study
    Bassett, JK ; MacInnis, RJ ; Yang, Y ; Hodge, AM ; Lynch, BM ; English, DR ; Giles, GG ; Milne, RL ; Jayasekara, H (WILEY, 2022-07-01)
    We examined associations between sex-specific alcohol intake trajectories and alcohol-related cancer risk using data from 22 756 women and 15 701 men aged 40 to 69 years at baseline in the Melbourne Collaborative Cohort Study. Alcohol intake for 10-year periods from age 20 until the decade encompassing recruitment, calculated using recalled beverage-specific frequency and quantity, was used to estimate group-based sex-specific intake trajectories. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for primary invasive alcohol-related cancer (upper aerodigestive tract, breast, liver and colorectum). Three distinct alcohol intake trajectories for women (lifetime abstention, stable light, increasing moderate) and six for men (lifetime abstention, stable light, stable moderate, increasing heavy, early decreasing heavy, late decreasing heavy) were identified. 2303 incident alcohol-related cancers were diagnosed during 485 525 person-years in women and 789 during 303 218 person-years in men. For men, compared with lifetime abstention, heavy intake (mean ≥ 60 g/day) at age 20 to 39 followed by either an early (from age 40 to 49) (early decreasing heavy; HR = 1.75, 95% CI: 1.25-2.44) or late decrease (from age 60 to 69) (late decreasing heavy; HR = 1.94, 95% CI: 1.28-2.93), and moderate intake (mean <60 g/day) at age 20 to 39 increasing to heavy intake in middle-age (increasing heavy; HR = 1.45, 95% CI: 1.06-1.97) were associated with increased risk of alcohol-related cancer. For women, compared with lifetime abstention, increasing intake from age 20 (increasing moderate) was associated with increased alcohol-related cancer risk (HR = 1.25, 95% CI: 1.06-1.48). Similar associations were observed for colorectal (men) and breast cancer. Heavy drinking during early adulthood might increase cancer risk later in life.
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    Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk
    Haas, CB ; Su, Y-R ; Petersen, P ; Wang, X ; Bien, SA ; Lin, Y ; Albanes, D ; Weinstein, SJ ; Jenkins, MA ; Figueiredo, JC ; Newcomb, PA ; Casey, G ; Le Marchand, L ; Campbell, PT ; Moreno, V ; Potter, JD ; Sakoda, LC ; Slattery, ML ; Chan, AT ; Li, L ; Giles, GG ; Milne, RL ; Gruber, SB ; Rennert, G ; Woods, MO ; Gallinger, SJ ; Berndt, S ; Hayes, RB ; Huang, W-Y ; Wolk, A ; White, E ; Nan, H ; Nassir, R ; Lindor, NM ; Lewinger, JP ; Kim, AE ; Conti, D ; Gauderman, WJ ; Buchanan, DD ; Peters, U ; Hsu, L (NATURE PORTFOLIO, 2022-11-07)
    Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.
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    Independent evaluation of melanoma polygenic risk scores in UK and Australian prospective cohorts
    Steinberg, J ; Lee, JY ; Wang, H ; Law, M ; Smit, A ; Nguyen-Dumont, T ; Giles, G ; Southey, M ; Milne, R ; Mann, G ; MacInnis, R ; Cust, A (OXFORD UNIV PRESS, 2021-09)
    BACKGROUND: Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS-based risk prediction, particularly assessment of calibration (comparing predicted to observed risks). OBJECTIVES: To evaluate PRS-based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry. METHODS: We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case-cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single-nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta-analysis (PRS68), 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment. RESULTS: Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62-0·68] and MCCS (E/O = 0·63, 95% CI 0·56-0·72). For UKB, calibration was improved by PRS adjustment, with PRS50-adjusted risks E/O = 0·91, 95% CI 0·87-0·95. The discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07-0·10, P < 0·0001), and higher than for PRS45-adjusted risks (Δ area under the curve 0·02-0·04, P < 0·001). CONCLUSIONS: A PRS derived from a larger, more diverse meta-analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations.