Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study

Suzanne C Dixon, Christina M Nagle, Aaron P Thrift, Paul DP Pharoah, Celeste Leigh Pearce, Wei Zheng, Jodie N Painter, Georgia Chenevix-Trench, Peter A Fasching, Matthias W Beckmann, Diether Lambrechts, Ignace Vergote, Sandrina Lambrechts, Els Van Nieuwenhuysen, Mary Anne Rossing, Jennifer A Doherty, Kristine G Wicklund, Jenny Chang-Claude, Anja Rudolph, Kirsten B Moysich, Kunle Odunsi, Marc T Goodman, Lynne R Wilkens, Pamela J Thompson, Yurii B Shvetsov, Thilo Dörk, Tjoung-Won Park-Simon, Peter Hillemanns, Natalia Bogdanova, Ralf Butzow, Heli Nevanlinna, Liisa M Pelttari, Arto Leminen, Francesmary Modugno, Roberta B Ness, Robert P Edwards, Joseph L Kelley, Florian Heitz, Beth Y Karlan, Susanne K Kjær, Estrid Høgdall, Allan Jensen, Ellen L Goode, Brooke L Fridley, Julie M Cunningham, Stacey J Winham, Graham G Giles, Fiona Bruinsma, Roger L Milne, Melissa C Southey, Michelle A T Hildebrandt, Xifeng Wu, Karen H Lu, Dong Liang, Douglas A Levine, Maria Bisogna, Joellen M Schildkraut, Andrew Berchuck, Daniel W Cramer, Kathryn L Terry, Elisa V Bandera, Sara H Olson, Helga B Salvesen, Liv Cecilie Thomsen, Reidun K Kopperud, Line Bjorge, Lambertus A Kiemeney, Leon F A G Massuger, Tanja Pejovic, Linda S Cook, Nhu D Le, Kenneth D Swenerton, Angela Brooks-Wilson, Linda E Kelemen, Jan Lubiński, Tomasz Huzarski, Jacek Gronwald, Janusz Menkiszak, Nicolas Wentzensen, Louise Brinton, Hannah Yang, Jolanta Lissowska, Claus K Høgdall, Lene Lundvall, Honglin Song, Jonathan P Tyrer, Ian Campbell, Diana Eccles, James Paul, Rosalind Glasspool, Nadeem Siddiqui, Alice S Whittemore, Weiva Sieh, Valerie McGuire, Joseph H Rothstein, Steven A Narod, Catherine Phelan, Harvey A Risch, John R McLaughlin, Hoda Anton-Culver, Argyrios Ziogas, Usha Menon, Simon A Gayther, Susan J Ramus, Aleksandra Gentry-Maharaj, Anna H Wu, Malcolm C Pike, Chiu-Chen Tseng, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Agnieszka Budzilowska, Beata Spiewankiewicz, Penelope M Webb

Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.