Melbourne School of Population and Global Health - Research Publications

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    Estimated dietary intake of polyphenols from cereal foods and associated lifestyle and demographic factors in the Melbourne Collaborative Cohort Study.
    Vingrys, K ; Mathai, ML ; Apostolopoulos, V ; Bassett, JK ; de Courten, M ; Stojanovska, L ; Millar, L ; Giles, GG ; Milne, RL ; Hodge, AM ; McAinch, AJ (Nature Portfolio, 2023-05-26)
    Cereal foods are consumed globally and are important sources of polyphenols with potential health benefits, yet dietary intakes are unclear. We aimed to calculate the dietary intakes of polyphenols from cereal foods in the Melbourne Collaborative Cohort Study (MCCS), and describe intakes by demographic and lifestyle factors. We estimated intakes of alkylresorcinols, lignans and phenolic acids in n = 39,892 eligible MCCS participants, using baseline dietary data (1990-1994) from a 121-item FFQ containing 17 cereal foods, matched to a polyphenol database developed from published literature and Phenol-Explorer Database. Intakes were estimated within groups according to lifestyle and demographic factors. The median (25th-75th percentile) intake of total polyphenols from cereal foods was 86.9 mg/day (51.4-155.8). The most consumed compounds were phenolic acids, with a median intake of 67.1 mg (39.5-118.8), followed by alkylresorcinols of 19.7 mg (10.8-34.6). Lignans made the smallest contribution of 0.50 mg (0.13-0.87). Higher polyphenol intakes were associated with higher relative socio-economic advantage and prudent lifestyles, including lower body mass index (BMI), non-smoking and higher physical activity scores. The findings based on polyphenol data specifically matched to the FFQ provide new information on intakes of cereal polyphenols, and how they might vary according to lifestyle and demographic factors.
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    Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.
    Yarmolinsky, J ; Robinson, JW ; Mariosa, D ; Karhunen, V ; Huang, J ; Dimou, N ; Murphy, N ; Burrows, K ; Bouras, E ; Smith-Byrne, K ; Lewis, SJ ; Galesloot, TE ; Kiemeney, LA ; Vermeulen, S ; Martin, P ; Albanes, D ; Hou, L ; Newcomb, PA ; White, E ; Wolk, A ; Wu, AH ; Le Marchand, L ; Phipps, AI ; Buchanan, DD ; International Lung Cancer Consortium, ; PRACTICAL Consortium, ; Zhao, SS ; Gill, D ; Chanock, SJ ; Purdue, MP ; Davey Smith, G ; Brennan, P ; Herzig, K-H ; Järvelin, M-R ; Amos, CI ; Hung, RJ ; Dehghan, A ; Johansson, M ; Gunter, MJ ; Tsilidis, KK ; Martin, RM (Elsevier BV, 2024-02)
    BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10-8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
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    Genetic and Environmental Causes of Variation in an Automated Breast Cancer Risk Factor Based on Mammographic Textures
    Ye, Z ; Dite, GS ; Nguyen, TL ; Macinnis, RJ ; Schmidt, DF ; Makalic, E ; Al-Qershi, OM ; Nguyen-Dumont, T ; Goudey, B ; Stone, J ; Dowty, JG ; Giles, GG ; Southey, MC ; Hopper, JL ; Li, S (AMER ASSOC CANCER RESEARCH, 2024-02-06)
    BACKGROUND: Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. METHODS: We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants. RESULTS: There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%). CONCLUSION: Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins. IMPACT: Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens.
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    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 (AMER ASSOC CANCER RESEARCH, 2024-01-09)
    BACKGROUND: We examined associations between adherence to adaptations of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and total, exposure-related and site-specific cancer risk. METHODS: A total of 20,001 participants ages 40 to 69 years at enrollment into the Melbourne Collaborative Cohort Study in 1990 to 1994, who had diet, body size, and lifestyle reassessed in 2003 to 2007 ("baseline"), were followed-up through June 2021. We constructed diet and standardized lifestyle scores based on core WCRF/AICR recommendations on diet, alcohol intake, body size and physical activity, and additional scores incorporating weight change, sedentary behavior, and smoking. Associations with cancer risk were estimated using Cox regression, adjusting for confounders. RESULTS: During follow-up (mean = 16 years), 4,710 incident cancers were diagnosed. For highest quintile ("most adherent") of the standardized lifestyle score, compared with lowest ("least adherent"), a HR of 0.82 [95% confidence interval (CI): 0.74-0.92] was observed for total cancer. This association was stronger with smoking included in the score (HR = 0.74; 95% CI: 0.67-0.81). A higher score was associated with lower breast and prostate cancer risk for the standardized score, and with lung, stomach, rectal, and pancreatic cancer risk when the score included smoking. Our analyses identified alcohol use, waist circumference and smoking as key drivers of associations with total cancer risk. CONCLUSIONS: Adherence to WCRF/AICR cancer prevention recommendations is associated with lower cancer risk. IMPACT: With <0.2% of our sample fully adherent to the recommendations, the study emphasizes the vast potential for preventing cancer through modulation of lifestyle habits.
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    Association of hormonal and reproductive factors with differentiated thyroid cancer risk in women: a pooled prospective cohort analysis.
    O'Grady, TJ ; Rinaldi, S ; Michels, KA ; Adami, H-O ; Buring, JE ; Chen, Y ; Clendenen, TV ; D'Aloisio, A ; DeHart, JC ; Franceschi, S ; Freedman, ND ; Gierach, GL ; Giles, GG ; Lacey, JV ; Lee, I-M ; Liao, LM ; Linet, MS ; McCullough, ML ; Patel, AV ; Prizment, A ; Robien, K ; Sandler, DP ; Stolzenberg-Solomon, R ; Weiderpass, E ; White, E ; Wolk, A ; Zheng, W ; Berrington de Gonzalez, A ; Kitahara, CM (Oxford University Press (OUP), 2024-02-01)
    BACKGROUND: The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results. METHODS: Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10-11 years; HR, 1.28; 95% CI, 1.00-1.64), younger (<40; HR, 1.31; 95% CI, 1.05-1.62) and older (≥55; HR, 1.33; 95% CI, 1.05-1.68) ages at menopause (vs 40-44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02-1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13-1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00-1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76-0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70-0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles. CONCLUSIONS: Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight.
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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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    Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
    Fernandez-Rozadilla, C ; Timofeeva, M ; Chen, Z ; Law, P ; Thomas, M ; Bien, S ; Diez-Obrero, V ; Li, L ; Fernandez-Tajes, J ; Palles, C ; Sherwood, K ; Harris, S ; Svinti, V ; McDonnell, K ; Farrington, S ; Studd, J ; Vaughan-Shaw, P ; Shu, X-O ; Long, J ; Cai, Q ; Guo, X ; Lu, Y ; Scacheri, P ; Studd, J ; Huyghe, J ; Harrison, T ; Shibata, D ; Haiman, C ; Devall, M ; Schumacher, F ; Melas, M ; Rennert, G ; Obon-Santacana, M ; Martin-Sanchez, V ; Moratalla-Navarro, F ; Oh, JH ; Kim, J ; Jee, SH ; Jung, KJ ; Kweon, S-S ; Shin, M-H ; Shin, A ; Ahn, Y-O ; Kim, D-H ; Oze, I ; Wen, W ; Matsuo, K ; Matsuda, K ; Tanikawa, C ; Ren, Z ; Gao, Y-T ; Jia, W-H ; Potter, J ; Jenkins, M ; Win, AK ; Pai, R ; Figueiredo, J ; Haile, R ; Gallinger, S ; Woods, M ; Newcomb, P ; Shibata, D ; Cheadle, J ; Kaplan, R ; Maughan, T ; Kerr, R ; Kerr, D ; Kirac, I ; Boehm, J ; Mecklin, L-P ; Jousilahti, P ; Knekt, P ; Aaltonen, L ; Rissanen, H ; Pukkala, E ; Eriksson, J ; Cajuso, T ; Hanninen, U ; Kondelin, J ; Palin, K ; Tanskanen, T ; Renkonen-Sinisalo, L ; Zanke, B ; Mannisto, S ; Albanes, D ; Weinstein, S ; Ruiz-Narvaez, E ; Palmer, J ; Buchanan, D ; Platz, E ; Visvanathan, K ; Ulrich, C ; Siegel, E ; Brezina, S ; Gsur, A ; Campbell, P ; Chang-Claude, J ; Hoffmeister, M ; Brenner, H ; Slattery, M ; Potter, J ; Tsilidis, K ; Schulze, M ; Gunter, M ; Murphy, N ; Castells, A ; Castellvi-Bel, S ; Moreira, L ; Arndt, V ; Shcherbina, A ; Stern, M ; Pardamean, B ; Bishop, T ; Giles, G ; Southey, M ; Idos, G ; McDonnell, K ; Abu-Ful, Z ; Greenson, J ; Shulman, K ; Lejbkowicz, F ; Offit, K ; Su, Y-R ; Steinfelder, R ; Keku, T ; van Guelpen, B ; Hudson, T ; Hampel, H ; Pearlman, R ; Berndt, S ; Hayes, R ; Martinez, ME ; Thomas, S ; Corley, D ; Pharoah, P ; Larsson, S ; Yen, Y ; Lenz, H-J ; White, E ; Li, L ; Doheny, K ; Pugh, E ; Shelford, T ; Chan, A ; Cruz-Correa, M ; Lindblom, A ; Shibata, D ; Joshi, A ; Schafmayer, C ; Scacheri, P ; Kundaje, A ; Nickerson, D ; Schoen, R ; Hampe, J ; Stadler, Z ; Vodicka, P ; Vodickova, L ; Vymetalkova, V ; Papadopoulos, N ; Edlund, C ; Gauderman, W ; Thomas, D ; Shibata, D ; Toland, A ; Markowitz, S ; Kim, A ; Gruber, S ; van Duijnhoven, F ; Feskens, E ; Sakoda, L ; Gago-Dominguez, M ; Wolk, A ; Naccarati, A ; Pardini, B ; FitzGerald, L ; Lee, SC ; Ogino, S ; Bien, S ; Kooperberg, C ; Li, C ; Lin, Y ; Prentice, R ; Qu, C ; Bezieau, S ; Tangen, C ; Mardis, E ; Yamaji, T ; Sawada, N ; Iwasaki, M ; Haiman, C ; Le Marchand, L ; Wu, A ; Qu, C ; McNeil, C ; Coetzee, G ; Hayward, C ; Deary, I ; Harris, S ; Theodoratou, E ; Reid, S ; Walker, M ; Ooi, LY ; Moreno, V ; Casey, G ; Gruber, S ; Tomlinson, I ; Zheng, W ; Dunlop, M ; Houlston, R ; Peters, U (NATURE PORTFOLIO, 2023-01)
    Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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    Causal relationships between breast cancer risk factors based on mammographic features
    Ye, Z ; Nguyen, TL ; Dite, GS ; Macinnis, RJ ; Schmidt, DF ; Makalic, E ; Al-Qershi, OM ; Bui, M ; Esser, VFC ; Dowty, JG ; Trinh, HN ; Evans, CF ; Tan, M ; Sung, J ; Jenkins, MA ; Giles, GG ; Southey, MC ; Hopper, JL ; Li, S (BMC, 2023-10-25)
    BACKGROUND: Mammogram risk scores based on texture and density defined by different brightness thresholds are associated with breast cancer risk differently and could reveal distinct information about breast cancer risk. We aimed to investigate causal relationships between these intercorrelated mammogram risk scores to determine their relevance to breast cancer aetiology. METHODS: We used digitised mammograms for 371 monozygotic twin pairs, aged 40-70 years without a prior diagnosis of breast cancer at the time of mammography, from the Australian Mammographic Density Twins and Sisters Study. We generated normalised, age-adjusted, and standardised risk scores based on textures using the Cirrus algorithm and on three spatially independent dense areas defined by increasing brightness threshold: light areas, bright areas, and brightest areas. Causal inference was made using the Inference about Causation from Examination of FAmilial CONfounding (ICE FALCON) method. RESULTS: The mammogram risk scores were correlated within twin pairs and with each other (r = 0.22-0.81; all P < 0.005). We estimated that 28-92% of the associations between the risk scores could be attributed to causal relationships between the scores, with the rest attributed to familial confounders shared by the scores. There was consistent evidence for positive causal effects: of Cirrus, light areas, and bright areas on the brightest areas (accounting for 34%, 55%, and 85% of the associations, respectively); and of light areas and bright areas on Cirrus (accounting for 37% and 28%, respectively). CONCLUSIONS: In a mammogram, the lighter (less dense) areas have a causal effect on the brightest (highly dense) areas, including through a causal pathway via textural features. These causal relationships help us gain insight into the relative aetiological importance of different mammographic features in breast cancer. For example our findings are consistent with the brightest areas being more aetiologically important than lighter areas for screen-detected breast cancer; conversely, light areas being more aetiologically important for interval breast cancer. Additionally, specific textural features capture aetiologically independent breast cancer risk information from dense areas. These findings highlight the utility of ICE FALCON and family data in decomposing the associations between intercorrelated disease biomarkers into distinct biological pathways.
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    A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
    Aglago, EK ; Kim, A ; Lin, Y ; Qu, C ; Evangelou, M ; Ren, Y ; Morrison, J ; Albanes, D ; Arndt, V ; Barry, EL ; Baurley, JW ; Berndt, S ; Bien, SA ; Bishop, DT ; Bouras, E ; Brenner, H ; Buchanan, DD ; Budiarto, A ; Carreras-Torres, R ; Casey, G ; Cenggoro, TW ; Chen, AT ; Chang-Claude, J ; Chen, X ; Conti, D ; Devall, M ; Diez-Obrero, V ; Dimou, N ; Drew, D ; Figueiredo, JC ; Gallinger, S ; Giles, GG ; Gruber, SB ; Gsur, A ; Gunter, MJ ; Hampel, H ; Harlid, S ; Hidaka, A ; Harrison, TA ; Hoffmeister, M ; Huyghe, JR ; Jenkins, MA ; Jordahl, K ; Joshi, AD ; Kawaguchi, ES ; Keku, TO ; Kundaje, A ; Larsson, SC ; Le Marchand, L ; Lewinger, JP ; Li, L ; Lynch, BM ; Mahesworo, B ; Mandic, M ; Obon-Santacana, M ; Morento, V ; Murphy, N ; Men, H ; Nassir, R ; Newcomb, PA ; Ogino, S ; Ose, J ; Pai, RK ; Palmer, JR ; Papadimitriou, N ; Pardamean, B ; Peoples, AR ; Platz, EA ; Potter, JD ; Prentice, RL ; Rennert, G ; Ruiz-Narvaez, E ; Sakoda, LC ; Scacheri, PC ; Schmit, SL ; Schoen, RE ; Shcherbina, A ; Slattery, ML ; Stern, MC ; Su, Y-R ; Tangen, CM ; Thibodeau, SN ; Thomas, DC ; Tian, Y ; Ulrich, CM ; van Duijnhoven, FJB ; Van Guelpen, B ; Visvanathan, K ; Vodicka, P ; Wang, J ; White, E ; Wolk, A ; Woods, MO ; Wu, AH ; Zemlianskaia, N ; Hsu, L ; Gauderman, WJ ; Peters, U ; Tsilidis, KK ; Campbell, PT (AMER ASSOC CANCER RESEARCH, 2023-08-01)
    UNLABELLED: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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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 ; Aittomakkiki, 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 ; Dork, T ; Dunning, AM ; Dwek, M ; Eccles, DM ; Engel, C ; Evans, DG ; Fasching, PA ; Gago-Dominguez, M ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gentry-Maharaj, A ; Geurts-Giele, WRR ; Giles, GG ; Glendon, G ; Goldberg, MS ; Garcia, EBG ; Guendert, M ; Guenel, 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 ; Investigators, A ; Jakimovska, M ; Jakubowska, A ; Jernstrom, H ; John, EM ; Kaaks, R ; Kitahara, CM ; Koutros, S ; Kraft, P ; Kristensen, VN ; Lacey, J ; Lambrechts, D ; Leone, M ; Lindblom, A ; 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, X-O ; Simard, J ; Southey, MC ; Stone, J ; Stoppa-Lyonnet, D ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teo, SH ; Teras, LR ; Terry, MB ; Thomassen, M ; Troester, MA ; Vachon, CM ; Vega, A ; Vreeswijk, MPG ; Wang, Q ; Wappenschmidt, B ; Weinberg, CR ; Wolk, A ; Zheng, W ; Feng, B ; Couch, FJ ; Spurdle, AB ; Easton, DF ; Goldgar, DE ; Michailidou, K ; Cutting, G (Wiley, 2023-09-14)
    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.