Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study

Frank Qian, Shengfeng Wang, Jonathan Mitchell, Lesley McGuffog, Daniel Barrowdale, Goska Leslie, Jan C Oosterwijk, Wendy K Chung, D Gareth Evans, Christoph Engel, Karin Kast, Cora M Aalfs, Muriel A Adank, Julian Adlard, Bjarni A Agnarsson, Kristiina Aittomäki, Elisa Alducci, Irene L Andrulis, Banu K Arun, Margreet G E M AusemsJacopo Azzollini, Emmanuelle Barouk-Simonet, Julian Barwell, Muriel Belotti, Javier Benitez, Andreas Berger, Ake Borg, Angela R Bradbury, Joan Brunet, Saundra S Buys, Trinidad Caldes, Maria A Caligo, Ian Campbell, Sandrine M Caputo, Jocelyne Chiquette, Kathleen B M Claes, J Margriet Collée, Fergus J Couch, Isabelle Coupier, Mary B Daly, Rosemarie Davidson, Orland Diez, Susan M Domchek, Alan Donaldson, Cecilia M Dorfling, Ros Eeles, Lidia Feliubadaló, Lenka Foretova, Jeffrey Fowler, Eitan Friedman, Mads Thomassen, GEMO Study Collaborators

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Abstrakt

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.

Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.

Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.

Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

OriginalsprogEngelsk
TidsskriftNational Cancer Institute. Journal (Print)
Vol/bind111
Udgave nummer4
Sider (fra-til)350-364
ISSN0027-8874
DOI
StatusUdgivet - 1. apr. 2019

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