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

Qian, F.; Wang, S.F.; Mitchell, J.; McGuffog, L.; Barrowdale, D.; Leslie, G.; ... ; EMBRACE (2019)

Article / Letter to editor

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/m(2) 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.

• All authors: Qian, F.; Wang, S.F.; Mitchell, J.; McGuffog, L.; Barrowdale, D.; Leslie, G.; Oosterwijk, J.C.; Chung, W.K.; Evans, D.G.; Engel, C.; Kast, K.; Aalfs, C.M.; Adank, M.A.; Adlard, J.; Agnarsson, B.A.; Aittomaki, K.; Alducci, E.; Andrulis, I.L.; Arun, B.K.; Ausems, M.G.E.M.; Azzollini, J.; Barouk-Simonet, E.; Barwell, J.; Belotti, M.; Benitez, J.; Berger, A.; Borg, A.; Bradbury, A.R.; Brunet, J.; Buys, S.S.; Caldes, T.; Caligo, M.A.; Campbell, I.; Caputo, S.M.; Chiquette, J.; Claes, K.B.M.; Collee, J.M.; Couch, F.J.; Coupier, I.; Daly, M.B.; Davidson, R.; Diez, O.; Domchek, S.M.; Donaldson, A.; Dorfling, C.M.; Eeles, R.; Feliubadalo, L.; Foretova, L.; Fowler, J.; Friedman, E.; Frost, D.; Ganz, P.A.; Garber, J.; Garcia-Barberan, V.; Glendon, G.; Godwin, A.K.; Garcia, E.B.G.; Gronwald, J.; Hahnen, E.; Hamann, U.; Henderson, A.; Hendricks, C.B.; Hopper, J.L.; Hulick, P.J.; Imyanitov, E.N.; Isaacs, C.; Izatt, L.; Izquierdo, A.; Jakubowska, A.; Kaczmarek, K.; Kang, E.; Karlan, B.Y.; Kets, C.M.; Kim, S.W.; Kim, Z.; Kwong, A.; Laitman, Y.; Lasset, C.; Lee, M.H.; Lee, J.W.; Lee, J.; Lester, J.; Lesueur, F.; Loud, J.T.; Lubinski, J.; Mebirouk, N.; Meijers-Heijboer, H.E.J.; Meindl, A.; Miller, A.; Montagna, M.; Mooij, T.M.; Morrison, P.J.; Mouret-Fourme, E.; Nathanson, K.L.; Neuhausen, S.L.; Nevanlinna, H.; Niederacher, D.; Nielsen, F.C.; Nussbaum, R.L.; Offit, K.; Olah, E.; Ong, K.R.; Ottini, L.; Park, S.K.; Peterlongo, P.; Pfeiler, G.; Phelan, C.M.; Poppe, B.; Pradhan, N.; Radice, P.; Ramus, S.J.; Rantala, J.; Robson, M.; Rodriguez, G.C.; Schmutzler, R.K.; Selkirk, C.G.H.; Shah, P.D.; Simard, J.; Singer, C.F.; Sokolowska, J.; Stoppa-Lyonnet, D.; Sutter, C.; Tan, Y.Y.; Teixeira, M.R.; Teo, S.H.; Terry, M.B.; Thomassen, M.; Tischkowitz, M.; Toland, A.E.; Tucker, K.M.; Tung, N.; Asperen, C.J. van; Engelen, K. van; Rensburg, E.J. van; Wang-Gohrke, S.; Wappenschmidt, B.; Weitzel, J.N.; Yannoukakos, D.; Greene, M.H.; Rookus, M.A.; Easton, D.F.; Chenevix-Trench, G.; Antoniou, A.C.; Goldgar, D.E.; Olopade, O.I.; Rebbeck, T.R.; Huo, D.Z.; GEMO Study Collaborators; HEBON; EMBRACE
• Date: 2019-04-01
• Journal: JNCI: Journal of the National Cancer Institute
• Volume: 111
• Issue: 4
• Pages: 350 - 364
• DOI: doi:10.1093/jnci/djy132