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Qian F , Wang S , Mitchell J , McGuffog L , Barrowdale D , Leslie G , Oosterwijk JC , Chung WK , Evans DG , Engel C , Kast K , Aalfs CM , Adank MA , Adlard J , Agnarsson BA , Aittomaki K , Alducci E , Andrulis IL , Arun BK , Ausems Mgem , Azzollini J , Barouk-Simonet E , Barwell J , Belotti M , Benitez J , Berger A , Borg A , Bradbury AR , Brunet J , Buys SS , Caldes T , Caligo MA , Campbell I , Caputo SM , Chiquette J , Claes KBM , Margriet Collee J , Couch FJ , Coupier I , Daly MB , Davidson R , Diez O , Domchek SM , Donaldson A , Dorfling CM , Eeles R , Feliubadalo L , Foretova L , Fowler J , Friedman E , Frost D , Ganz PA , Garber J , Garcia-Barberan V , Glendon G , Godwin AK , Gomez Garcia EB , Gronwald J , Hahnen E , Hamann U , Henderson A , Hendricks CB , Hopper JL , Hulick PJ , Imyanitov EN , Isaacs C , Izatt L , Izquierdo A , Jakubowska A , Kaczmarek K , Kang E , Karlan BY , Kets CM , Kim SW , Kim Z , Kwong A , Laitman Y , Lasset C , Hyuk Lee M , Won Lee J , Lee J , Lester J , Lesueur F , Loud JT , Lubinski J , Mebirouk N , Meijers-Heijboer HEJ , Meindl A , Miller A , Montagna M , Mooij TM , Morrison PJ , Mouret-Fourme E , Nathanson KL , Neuhausen SL , Nevanlinna H , Niederacher D , Nielsen FC , Nussbaum RL , Offit K , Olah E , Ong KR , Ottini L , Park SK , Peterlongo P , Pfeiler G , Phelan CM , Poppe B , Pradhan N , Radice P , Ramus SJ , Rantala J , Robson M , Rodriguez GC , Schmutzler RK , Hutten Selkirk CG , Shah PD , Simard J , Singer CF , Sokolowska J , Stoppa-Lyonnet D , Sutter C , Yen Tan Y , Teixeira RM , Teo SH , Terry MB , Thomassen M , Tischkowitz M , Toland AE , Tucker KM , Tung N , van Asperen CJ , van Engelen K , van Rensburg EJ , Wang-Gohrke S , Wappenschmidt B , Weitzel JN , Yannoukakos D , Gemo Study Collaborators , Hebon , Embrace , Greene MH , Rookus MA , Easton DF , Chenevix-Trench G , Antoniou AC , Goldgar DE , Olopade OI , Rebbeck TR , Huo D
Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study
J Natl Cancer Inst. 2019 Apr 1;111(4) :350-364
PMID: 30312457    PMCID: PMC6449171    URL: https://www.ncbi.nlm.nih.gov/pubmed/30312457
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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.
Notes
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 Aittomaki, Kristiina Alducci, Elisa Andrulis, Irene L Arun, Banu K Ausems, Margreet G E M 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 B M Margriet Collee, J Couch, Fergus J Coupier, Isabelle Daly, Mary B Davidson, Rosemarie Diez, Orland Domchek, Susan M Donaldson, Alan Dorfling, Cecilia M Eeles, Ros Feliubadalo, Lidia Foretova, Lenka Fowler, Jeffrey Friedman, Eitan Frost, Debra Ganz, Patricia A Garber, Judy Garcia-Barberan, Vanesa Glendon, Gord Godwin, Andrew K Gomez 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, Angel 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 E J 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 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 eng 10118/Cancer Research UK/United Kingdom P50 CA116201/CA/NCI NIH HHS/ J Natl Cancer Inst. 2019 Apr 1;111(4):350-364. doi: 10.1093/jnci/djy132.