Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Kconfab Investigators ,Hebon Investigators

doi:10.1038/s41416-019-0492-8

Kconfab Investigators , Hebon Investigators

Open Access

https://doi.org/10.1038/s41416-019-0492-8

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Abstract

BackgroundHeight and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.MethodsWe applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models.ResultsObserved height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05).ConclusionOur observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Highlights

Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown
Observed and predicted height on risk of ovarian cancer In the survival modelling of ovarian cancer risk, age was used as the underlying timescale and the numbers of individuals retained in the analysis were 20535, 14647, 7375, and 2832 at ages 30, 40, 50, and 60 years, respectively, suggesting that statistical power for the late age is limited
Our finding of a positive association between BMI and overall ovarian cancer risk in BRCA1 and BRCA2 mutation carriers is corroborated by several prior studies in the general population.[12,14,15,33]

Summary

Introduction

Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population. Unlike breast or colorectal cancer, there is no proven screening method for ovarian cancer to identify early disease and initiate treatment to improve survival.[3,4] Family history, oral contraceptive use, parity, body mass index (BMI), and genetic variants are potentially useful in estimating lifetime risk.[1] In particular, inherited BRCA1 and BRCA2 mutations are associated with increased lifetime risk of ovarian cancer and account for ~10–15% of overall disease incidence.[5,6,7] among mutation carriers, age at diagnosis is variable. Penetrance of BRCA1/2 mutations is likely modified by other genetic variants and lifestyle or reproductive factors.[8,9] Investigation of these factors could aid in implementation of strategies to reduce ovarian cancer risk among mutation carriers

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