Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.
Frank Qian,
Matti A Rookus,
Goska Leslie,
Harvey A Risch,
Mark H Greene,
Cora M Aalfs,
Muriel A Adank,
Julian Adlard,
Bjarni A Agnarsson,
Munaza Ahmed,
Kristiina Aittomäki,
Irene L Andrulis,
Norbert Arnold,
Banu K Arun,
Margreet G E M Ausems,
Jacopo Azzollini,
Daniel Barrowdale,
Julian Barwell,
Javier Benitez,
Katarzyna Białkowska,
Valérie Bonadona,
Julika Borde,
Ake Borg,
Angela R Bradbury,
Joan Brunet,
Saundra S Buys,
Trinidad Caldés,
Maria A Caligo,
Ian Campbell,
Jonathan Carter,
Jocelyne Chiquette,
Wendy K Chung,
Kathleen B M Claes,
J Margriet Collée,
Marie-Agnès Collonge-Rame,
Fergus J Couch,
Mary B Daly,
Capucine Delnatte,
Orland Diez,
Susan M Domchek,
Cecilia M Dorfling,
Jacqueline Eason,
Douglas F Easton,
Ros Eeles,
Christoph Engel,
D Gareth Evans,
Laurence Faivre,
Lidia Feliubadaló,
Lenka Foretova,
Eitan Friedman,
Debra Frost,
Patricia A Ganz,
Judy Garber,
Vanesa Garcia-Barberan,
Andrea Gehrig,
Gord Glendon,
Andrew K Godwin,
Encarna B Gómez Garcia,
Ute Hamann,
Jan Hauke,
John L Hopper,
Peter J Hulick,
Evgeny N Imyanitov,
Claudine Isaacs,
Louise Izatt,
Anna Jakubowska,
Ramunas Janavicius,
Esther M John,
Beth Y Karlan,
Carolien M Kets,
Yael Laitman,
Conxi Lázaro,
Dominique Leroux,
Jenny Lester,
Fabienne Lesueur,
Jennifer T Loud,
Jan Lubiński,
Alicja Łukomska,
Lesley McGuffog,
Noura Mebirouk,
Hanne E J Meijers-Heijboer,
Alfons Meindl,
Austin Miller,
Marco Montagna,
Thea M Mooij,
Emmanuelle Mouret-Fourme,
Katherine L Nathanson,
Bita Nehoray,
Susan L Neuhausen,
Heli Nevanlinna,
Finn C Nielsen,
Kenneth Offit,
Edith Olah,
Kai-Ren Ong,
Jan C Oosterwijk,
Laura Ottini,
Michael T Parsons,
Paolo Peterlongo,
Georg Pfeiler,
Nisha Pradhan,
Paolo Radice,
Susan J Ramus,
Johanna Rantala,
Gad Rennert,
Mark Robson,
Gustavo C Rodriguez,
Ritu Salani,
Maren T Scheuner,
Rita K Schmutzler,
Payal D Shah,
Lucy E Side,
Jacques Simard,
Christian F Singer,
Doris Steinemann,
Dominique Stoppa-Lyonnet,
Yen Yen Tan,
Manuel R Teixeira,
Mary Beth Terry,
Mads Thomassen,
Marc Tischkowitz,
Silvia Tognazzo,
Amanda E Toland,
Nadine Tung,
Christi J van Asperen,
Klaartje van Engelen,
Elizabeth J van Rensburg,
Laurence Venat-Bouvet,
Jeroen Vierstraete,
Gabriel Wagner,
Lisa Walker,
Jeffrey N Weitzel,
Drakoulis Yannoukakos,
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Antonis C Antoniou,
David E Goldgar,
Olufunmilayo I Olopade,
Georgia Chenevix-Trench,
Timothy R Rebbeck,
Dezheng Huo,
Abstract
METHODS
We 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.
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.
RESULTS
Observed 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).
BACKGROUND
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.