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Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

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

BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSION: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.

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