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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Qian, Frank 
Wang, Shengfeng 
Mitchell, Jonathan 
McGuffog, Lesley 
Barrowdale, Daniel 

Abstract

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.

Description

Keywords

Adult, BRCA1 Protein, BRCA2 Protein, Body Height, Body Mass Index, Breast Neoplasms, Female, Genetic Predisposition to Disease, Humans, Mendelian Randomization Analysis, Mutation, Polymorphism, Single Nucleotide, Prognosis, Risk Factors

Journal Title

J Natl Cancer Inst

Conference Name

Journal ISSN

0027-8874
1460-2105

Volume Title

111

Publisher

Oxford University Press (OUP)
Sponsorship
Cancer Research Uk (None)
Cancer Research UK (20861)
European Commission (223175)
National Cancer Institute (R01CA128978)
Cancer Research UK (11990)
Cancer Research UK (12014)
Cancer Research UK (10118)
Wellcome Trust (203477/Z/16/Z)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)