Melbourne School of Population and Global Health - Research Publications

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    Mental disorders and discrimination: A prospective cohort study of young twin pairs in Germany.
    Calais-Ferreira, L ; Armstrong, G ; Hahn, E ; Newton-Howes, G ; Foulds, J ; Hopper, JL ; Spinath, FM ; Kurdyak, P ; Young, JT (Elsevier BV, 2024-03)
    BACKGROUND: Mental disorders and perceived discrimination share common risk factors. The association between having a mental disorder and experiencing discrimination is well-known, but the extent to which familial factors, such as genetic and shared environmental factors, might confound this association, including sex differences in familial confounding, remains unexplored. AIMS: We investigated potential unmeasured familial confounding in the association between mental disorders and perceived discrimination using a matched twin study design. METHOD: We examined data from 2044 same-sex twin pairs (n = 4088) aged 16-25 years from the German population-based study 'TwinLife'. We applied random-effects logistic regression to within-individual and within-and-between pair models of the association between mental disorder and perceived discrimination, and used likelihood ratio tests (LRTs) to compare these models. Multivariable models were adjusted for body mass index, educational attainment, and life satisfaction. RESULTS: There were 322 (8.1%) participants with a diagnosed mental disorder, and 15% (n = 604) of the cohort reported having experienced discrimination in the previous 12 months. Mental disorder and discrimination were associated in the adjusted within-individual model (adjusted odds ratio = 2.19, 95% confidence interval: 1.42-3.39, P<0.001). However, the within-and-between pair model showed that this association was explained by the within-pair mean (aOR = 4.24, 95% CI: 2.17-8.29, P<0.001) and not the within-pair difference (aOR = 1.26, 95% CI: 0.70-2.28, P = 0.4) of mental disorder. Therefore, this association was mostly explained by familial confounding, which is also supported by the LRTs for the unadjusted and adjusted models (P<0.001 and P = 0.03, respectively). This familial confounding was more prominent for males than females. CONCLUSIONS: Our findings show that the association between mental disorder and discrimination is at least partially explained by unmeasured familial factors. Designing family-based healthcare models and incorporating family members in interventions targeted at ameliorating mental ill-health and experiences of discrimination among adolescents may improve efficacy.
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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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    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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    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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    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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    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 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.