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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    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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    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 ; 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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    Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel
    Levi, H ; Carmi, S ; Rosset, S ; Yerushalmi, R ; Zick, A ; Yablonski-Peretz, T ; Wang, Q ; Bolla, MK ; Dennis, J ; Michailidou, K ; Lush, M ; Ahearn, T ; Andrulis, IL ; Anton-Culver, H ; Antoniou, AC ; Arndt, V ; Augustinsson, A ; Auvinen, P ; Beane Freeman, L ; Beckmann, M ; Behrens, S ; Bermisheva, M ; Bodelon, C ; Bogdanova, N ; Bojesen, SE ; Brenner, H ; Byers, H ; Camp, N ; Castelao, J ; Chang-Claude, J ; Chirlaque, M-D ; Chung, W ; Clarke, C ; Collee, MJ ; Colonna, S ; Couch, F ; Cox, A ; Cross, SS ; Czene, K ; Daly, M ; Devilee, P ; Dork, T ; Dossus, L ; Eccles, DM ; Eliassen, AH ; Eriksson, M ; Evans, G ; Fasching, P ; Fletcher, O ; Flyger, H ; Fritschi, L ; Gabrielson, M ; Gago-Dominguez, M ; Garcia-Closas, M ; Garcia-Saenz, JA ; Genkinger, J ; Giles, GG ; Goldberg, M ; Guenel, P ; Hall, P ; Hamann, U ; He, W ; Hillemanns, P ; Hollestelle, A ; Hoppe, R ; Hopper, J ; Jakovchevska, S ; Jakubowska, A ; Jernstrom, H ; John, E ; Johnson, N ; Jones, M ; Vijai, J ; Kaaks, R ; Khusnutdinova, E ; Kitahara, C ; Koutros, S ; Kristensen, V ; Kurian, AW ; Lacey, J ; Lambrechts, D ; Le Marchand, L ; Lejbkowicz, F ; Lindblom, A ; Loibl, S ; Lori, A ; Lubinski, J ; Mannermaa, A ; Manoochehri, M ; Mavroudis, D ; Menon, U ; Mulligan, A ; Murphy, R ; Nevelsteen, I ; Newman, WG ; Obi, N ; O'Brien, K ; Offit, K ; Olshan, A ; Plaseska-Karanfilska, D ; Olson, J ; Panico, S ; Park-Simon, T-W ; Patel, A ; Peterlongo, P ; Rack, B ; Radice, P ; Rennert, G ; Rhenius, V ; Romero, A ; Saloustros, E ; Sandler, D ; Schmidt, MK ; Schwentner, L ; Shah, M ; Sharma, P ; Simard, J ; Southey, M ; Stone, J ; Tapper, WJ ; Taylor, J ; Teras, L ; Toland, AE ; Troester, M ; Truong, T ; van der Kolk, LE ; Weinberg, C ; Wendt, C ; Yang, XR ; Zheng, W ; Ziogas, A ; Dunning, AM ; Pharoah, P ; Easton, DF ; Ben-Sachar, S ; Elefant, N ; Shamir, R ; Elkon, R (BMJ PUBLISHING GROUP, 2023-12)
    BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
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    Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes
    Mahmood, K ; Thomas, M ; Qu, C ; Hsu, L ; Buchanan, DD ; Peters, U (W B SAUNDERS CO-ELSEVIER INC, 2023-10)