Height and Body Mass Index as Modifiers of Breast Cancer Risk in <i>BRCA1</i>/<i>2</i> Mutation Carriers: A Mendelian Randomization Study
Authors: Frank Qian, Shengfeng Wang, Jonathan Mitchell, Lesley McGuffog, Daniel Barrowdale, Goska Leslie, Jan C Oosterwijk, Wendy K Chung, D Gareth Evans, Christoph Engel, Karin Kast, Cora M Aalfs, Muriel A Adank, Julian Adlard, Bjarni A Agnarsson, Kristiina Aittomäki, Elisa Alducci, Irene L Andrulis, Banu K Arun, Margreet G E M Ausems, Jacopo Azzollini, Emmanuelle Barouk-Simonet, Julian Barwell, Muriel Belotti, Javier Benitez, Andreas Berger, Ake Borg, Angela R Bradbury, Joan Brunet, Saundra S Buys, Trinidad Caldes, Maria A Caligo, Ian Campbell, Sandrine M Caputo, Jocelyne Chiquette, Kathleen B M Claes, J Margriet Collée, Fergus J Couch, Isabelle Coupier, Mary B Daly, Rosemarie Davidson, Orland Diez, Susan M Domchek, Alan Donaldson, Cecilia M Dorfling, Ros Eeles, Lidia Feliubadaló, Lenka Foretova, Jeffrey Fowler, Eitan Friedman, Debra Frost, Patricia A Ganz, Judy Garber, Vanesa Garcia-Barberan, Gord Glendon, Andrew K Godwin, Encarna B Gómez Garcia, Jacek Gronwald, Eric Hahnen, Ute Hamann, Alex Henderson, Carolyn B Hendricks, John L Hopper, Peter J Hulick, Evgeny N Imyanitov, Claudine Isaacs, Louise Izatt, Ángel Izquierdo, Anna Jakubowska, Katarzyna Kaczmarek, Eunyoung Kang, Beth Y Karlan, Carolien M Kets, Sung-Won Kim, Zisun Kim, Ava Kwong, Yael Laitman, Christine Lasset, Min Hyuk Lee, Jong Won Lee, Jihyoun Lee, Jenny Lester, Fabienne Lesueur, Jennifer T Loud, Jan Lubinski, Noura Mebirouk, Hanne E J Meijers-Heijboer, Alfons Meindl, Austin Miller, Marco Montagna, Thea M Mooij, Patrick J Morrison, Emmanuelle Mouret-Fourme, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn C Nielsen, Robert L Nussbaum, Kenneth Offit, Edith Olah, Kai-Ren Ong, Laura Ottini, Sue K Park, Paolo Peterlongo, Georg Pfeiler, Catherine M Phelan, Bruce Poppe, Nisha Pradhan, Paolo Radice, Susan J Ramus, Johanna Rantala, Mark Robson, Gustavo C Rodriguez, Rita K Schmutzler, Christina G Hutten Selkirk, Payal D Shah, Jacques Simard, Christian F Singer, Johanna Sokolowska, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, R Manuel Teixeira, Soo H Teo, Mary Beth Terry, Mads Thomassen, Marc Tischkowitz, Amanda E Toland, Katherine M Tucker, Nadine Tung, Christi J van Asperen, Klaartje van Engelen, Elizabeth J van Rensburg, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N Weitzel, Drakoulis Yannoukakos, Mark H Greene, Matti A Rookus, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, David E Goldgar, Olufunmilayo I Olopade, Timothy R Rebbeck, Dezheng Huo
Journal: JNCI Journal of the National Cancer Institute (2018)

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. 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. 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. 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.