Dataset Information

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

ABSTRACT: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

SUBMITTER: Kapoor PM

PROVIDER: S-EPMC7936056 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

Kapoor Pooja Middha PM Mavaddat Nasim N Choudhury Parichoy Pal PP Wilcox Amber N AN Lindström Sara S Behrens Sabine S Michailidou Kyriaki K Dennis Joe J Bolla Manjeet K MK Wang Qin Q Jung Audrey A Abu-Ful Zomoroda Z Ahearn Thomas T Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Aronson Kristan J KJ Auer Paul L PL Freeman Laura E Beane LEB Becher Heiko H Beckmann Matthias W MW Beeghly-Fadiel Alicia A Benitez Javier J Bernstein Leslie L Bojesen Stig E SE Brauch Hiltrud H Brenner Hermann H Brüning Thomas T Cai Qiuyin Q Campa Daniele D Canzian Federico F Carracedo Angel A Carter Brian D BD Castelao Jose E JE Chanock Stephen J SJ Chatterjee Nilanjan N Chenevix-Trench Georgia G Clarke Christine L CL Couch Fergus J FJ Cox Angela A Cross Simon S SS Czene Kamila K Dai James Y JY Earp H Shelton HS Ekici Arif B AB Eliassen A Heather AH Eriksson Mikael M Evans D Gareth DG Fasching Peter A PA Figueroa Jonine J Fritschi Lin L Gabrielson Marike M Gago-Dominguez Manuela M Gao Chi C Gapstur Susan M SM Gaudet Mia M MM Giles Graham G GG González-Neira Anna A Guénel Pascal P Haeberle Lothar L Haiman Christopher A CA Håkansson Niclas N Hall Per P Hamann Ute U Hatse Sigrid S Heyworth Jane J Holleczek Bernd B Hoover Robert N RN Hopper John L JL Howell Anthony A Hunter David J DJ John Esther M EM Jones Michael E ME Kaaks Rudolf R Keeman Renske R Kitahara Cari M CM Ko Yon-Dschun YD Koutros Stella S Kurian Allison W AW Lambrechts Diether D Le Marchand Loic L Lee Eunjung E Lejbkowicz Flavio F Linet Martha M Lissowska Jolanta J Llaneza Ana A MacInnis Robert J RJ Martinez Maria Elena ME Maurer Tabea T McLean Catriona C Neuhausen Susan L SL Newman William G WG Norman Aaron A O'Brien Katie M KM Olshan Andrew F AF Olson Janet E JE Olsson Håkan H Orr Nick N Perou Charles M CM Pita Guillermo G Polley Eric C EC Prentice Ross L RL Rennert Gad G Rennert Hedy S HS Ruddy Kathryn J KJ Sandler Dale P DP Saunders Christobel C Schoemaker Minouk J MJ Schöttker Ben B Schumacher Fredrick F Scott Christopher C Scott Rodney J RJ Shu Xiao-Ou XO Smeets Ann A Southey Melissa C MC Spinelli John J JJ Stone Jennifer J Swerdlow Anthony J AJ Tamimi Rulla M RM Taylor Jack A JA Troester Melissa A MA Vachon Celine M CM van Veen Elke M EM Wang Xiaoliang X Weinberg Clarice R CR Weltens Caroline C Willett Walter W Winham Stacey J SJ Wolk Alicja A Yang Xiaohong R XR Zheng Wei W Ziogas Argyrios A Dunning Alison M AM Pharoah Paul D P PDP Schmidt Marjanka K MK Kraft Peter P Easton Douglas F DF Milne Roger L RL García-Closas Montserrat M Chang-Claude Jenny J

Journal of the National Cancer Institute 20210301 3

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviatio ...[more]

PMID: 32359158

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Project description:Background:Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors. Methods:Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status. Results:The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction?=?0.009), adult height (P-interaction?=?0.025) and current use of combined MHT (P-interaction?=?0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P?=?0.013 for global and 0.18 for tail-based tests). Conclusions:The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.

Dataset Information

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

Publications

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

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