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Height and body mass index as modifiers of breast cancer risk in BRCA1/2 mutation carriers: A mendelian randomization study

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.

Type Journal
ISBN 0027-8874
Authors Qian, F.; Wang, S.; 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, Mgem; 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.; Margriet Collee, J.; 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.; Gomez Garcia, E. B.; 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.; Hyuk Lee, M.; Won Lee, J.; 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., et al.
Publisher Name JNCI-Journal of the National Cancer Institute
Published Date 2019-04-01
Published Volume 111
Published Issue 4
Published Pages 350-364
Status Published in-print
DOI 10.1093/jnci/djy132
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/?term=30312457