Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Qian, F.; Rookus, M. A.; Leslie, G.; Risch, H. A.; Greene, M. H.; Aalfs, C. M.; Adank, M. A.; Adlard, J.; Agnarsson, B. A.; Ahmed, M.; Aittomaki, K.; Andrulis, I. L.; Arnold, N.; Arun, B. K.; Ausems, M. G. E. M.; Azzollini, J.; Barrowdale, D.; Barwell, J.; Benitez, J.; Bialkowska, K.; Bonadona, V.; Borde, J.; Borg, A.; Bradbury, A. R.; Brunet, J.; Buys, S. S.; Caldes, T.; Caligo, M. A.; Campbell, I.; Carter, J.; Chiquette, J.; Chung, W. K.; Claes, K. B. M.; Collee, J. M.; Collonge-Rame, M. -A.; Couch, F. J.; Daly, M. B.; Delnatte, C.; Diez, O.; Domchek, S. M.; Dorfling, C. M.; Eason, J.; Easton, D. F.; Eeles, R.; Engel, C.; Evans, D. G.; Faivre, L.; Feliubadalo, L.; Foretova, L.; Friedman, E.; Frost, D.; Ganz, P. A.; Garber, J.; Garcia-Barberan, V.; Gehrig, A.; Glendon, G.; Godwin, A. K.; Gomez Garcia, E. B.; Hamann, U.; Hauke, J.; Hopper, J. L.; Hulick, P. J.; Imyanitov, E. N.; Isaacs, C.; Izatt, L.; Jakubowska, A.; Janavicius, R.; John, E. M.; Karlan, B. Y.; Kets, C. M.; Laitman, Y.; Lazaro, C.; Leroux, D.; Lester, J.; Lesueur, F.; Loud, J. T.; Lubinski, J.; Lukomska, A.; Mcguffog, L.; Mebirouk, N.; Meijers-Heijboer, H. E. J.; Meindl, A.; Miller, A.; Montagna, M.; Mooij, T. M.; Mouret-Fourme, E.; Nathanson, K. L.; Nehoray, B.; Neuhausen, S. L.; Nevanlinna, H.; Nielsen, F. C.; Offit, K.; Olah, E.; Ong, K. -R.; Oosterwijk, J. C.; Ottini, L.; Parsons, M. T.; Peterlongo, P.; Pfeiler, G.; Pradhan, N.; Radice, P.; Ramus, S. J.; Rantala, J.; Rennert, G.; Robson, M.; Rodriguez, G. C.; Salani, R.; Scheuner, M. T.; Schmutzler, R. K.; Shah, P. D.; Side, L. E.; Simard, J.; Singer, C. F.; Steinemann, D.; Stoppa-Lyonnet, D.; Tan, Y. Y.; Teixeira, M. R.; Terry, M. B.; Thomassen, M.; Tischkowitz, M.; Tognazzo, S.; Toland, A. E.; Tung, N.; van Asperen, C. J.; van Engelen, K.; van Rensburg, E. J.; Venat-Bouvet, L.; Vierstraete, J.; Wagner, G.; Walker, L.; Weitzel, J. N.; Yannoukakos, D.; Antoniou, A. C.; Goldgar, D. E.; Olopade, O. I.; Chenevix-Trench, G.; Rebbeck, T. R.; Huo, D.; on behalf of CIMBA,

doi:10.1038/s41416-019-0492-8

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. 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. 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). 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.

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers / Qian, F.; Rookus, M. A.; Leslie, G.; Risch, H. A.; Greene, M. H.; Aalfs, C. M.; Adank, M. A.; Adlard, J.; Agnarsson, B. A.; Ahmed, M.; Aittomaki, K.; Andrulis, I. L.; Arnold, N.; Arun, B. K.; Ausems, M. G. E. M.; Azzollini, J.; Barrowdale, D.; Barwell, J.; Benitez, J.; Bialkowska, K.; Bonadona, V.; Borde, J.; Borg, A.; Bradbury, A. R.; Brunet, J.; Buys, S. S.; Caldes, T.; Caligo, M. A.; Campbell, I.; Carter, J.; Chiquette, J.; Chung, W. K.; Claes, K. B. M.; Collee, J. M.; Collonge-Rame, M. -A.; Couch, F. J.; Daly, M. B.; Delnatte, C.; Diez, O.; Domchek, S. M.; Dorfling, C. M.; Eason, J.; Easton, D. F.; Eeles, R.; Engel, C.; Evans, D. G.; Faivre, L.; Feliubadalo, L.; Foretova, L.; Friedman, E.; Frost, D.; Ganz, P. A.; Garber, J.; Garcia-Barberan, V.; Gehrig, A.; Glendon, G.; Godwin, A. K.; Gomez Garcia, E. B.; Hamann, U.; Hauke, J.; Hopper, J. L.; Hulick, P. J.; Imyanitov, E. N.; Isaacs, C.; Izatt, L.; Jakubowska, A.; Janavicius, R.; John, E. M.; Karlan, B. Y.; Kets, C. M.; Laitman, Y.; Lazaro, C.; Leroux, D.; Lester, J.; Lesueur, F.; Loud, J. T.; Lubinski, J.; Lukomska, A.; Mcguffog, L.; Mebirouk, N.; Meijers-Heijboer, H. E. J.; Meindl, A.; Miller, A.; Montagna, M.; Mooij, T. M.; Mouret-Fourme, E.; Nathanson, K. L.; Nehoray, B.; Neuhausen, S. L.; Nevanlinna, H.; Nielsen, F. C.; Offit, K.; Olah, E.; Ong, K. -R.; Oosterwijk, J. C.; Ottini, L.; Parsons, M. T.; Peterlongo, P.; Pfeiler, G.; Pradhan, N.; Radice, P.; Ramus, S. J.; Rantala, J.; Rennert, G.; Robson, M.; Rodriguez, G. C.; Salani, R.; Scheuner, M. T.; Schmutzler, R. K.; Shah, P. D.; Side, L. E.; Simard, J.; Singer, C. F.; Steinemann, D.; Stoppa-Lyonnet, D.; Tan, Y. Y.; Teixeira, M. R.; Terry, M. B.; Thomassen, M.; Tischkowitz, M.; Tognazzo, S.; Toland, A. E.; Tung, N.; van Asperen, C. J.; van Engelen, K.; van Rensburg, E. J.; Venat-Bouvet, L.; Vierstraete, J.; Wagner, G.; Walker, L.; Weitzel, J. N.; Yannoukakos, D.; Antoniou, A. C.; Goldgar, D. E.; Olopade, O. I.; Chenevix-Trench, G.; Rebbeck, T. R.; Huo, D.; on behalf of, Cimba. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - 121:2(2019), pp. 180-192. [10.1038/s41416-019-0492-8]