Abstract 881: Association of adult body mass index and height with risk of ovarian cancer in 39,000 women: Results of a Mendelian randomization study

Abstract

Abstract INTRODUCTION: Observational studies have reported positive associations between higher body mass index (BMI) and risks of borderline ovarian tumors and non-high grade serous ovarian cancer (non-HGSC), but the lack of association observed for HGSC may be due to bias arising from weight loss before diagnosis. Observational studies also suggest a positive association between greater height and ovarian cancer risk, but confounding factors may be obscuring the true relationship. The Mendelian randomization (MR) technique uses genetic markers as proxies for environmental risk factors, and can overcome the limitations of bias and confounding which affect observational studies. AIM / METHODS: This study used MR to elucidate the relationship between body size (BMI and height) and risk of ovarian cancer. We pooled data from 16,395 cases and 23,003 controls, all genetically European, from 39 studies in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS) for each trait, summing trait-increasing alleles at 31 single nucleotide polymorphisms (SNPs) associated with BMI and 609 SNPs associated with height in genome-wide association studies, weighting alleles by published β-coefficients for their effect on the trait. Each GRS was a strong instrument for the trait (F-statistics 33.8 [BMI] and 516 [height]). In a two-stage predictor substitution MR approach, we used multivariate logistic regression to model case-control status on body size predicted by each GRS. Study-specific estimates per 5-unit increase in predicted BMI or height were pooled to generate pooled odds ratios (OR) and 95% confidence intervals (CI) using random-effects meta-analysis. Our primary hypotheses were that genetic BMI would be associated with increased risk of non-HGSC but not HGSC and genetic height would be associated with increased risk of ovarian cancer overall. RESULTS: Higher genetically-predicted BMI was associated with increased risk of non-HGSC cancer (OR 1.37, 95% CI 1.02-1.83 per 5-unit increase) but not HGSC (OR 1.05, 95% CI 0.83-1.33). In secondary analyses stratified by behavior/subtype, the strongest association was seen for low grade/borderline serous cancers (OR 2.02, 95% CI 1.24-3.30). Women with greater genetically-predicted height had a modestly increased risk of all (invasive and borderline) ovarian tumors (OR 1.06, 95% CI 1.01-1.11 per 5 cm). In secondary analyses stratified by histologic subtype, the strongest association was seen for clear cell cancers (OR 1.20, 95% CI 1.04-1.38). CONCLUSION: This study is the first to apply MR to investigate ovarian cancer risk factors. These data confirm results from epidemiologic studies, suggesting that obesity is causally associated with non-HGSC, but does not increase risk of the most common HGSC subtype. They also support an association between height and ovarian cancer. Citation Format: Suzanne C. Dixon, Christina M. Nagle, Aaron P. Thrift, Paul D.P Pharoah, Ailith Pirie, Celeste Leigh Pearce, Wei Zheng, Penelope M. Webb, for the Ovarian Cancer Association Consortium. Association of adult body mass index and height with risk of ovarian cancer in 39,000 women: Results of a Mendelian randomization study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 881. doi:10.1158/1538-7445.AM2015-881