Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women

Xiaoliang Wang, Pooja Middha Kapoor, Paul L. Auer, Joe Dennis, Alison M. Dunning, Qin Wang, Michael Lush, Kyriaki Michailidou, Manjeet K. Bolla, Kristan J. Aronson, Rachel A. Murphy, Angela Brooks-wilson, Derrick G. Lee, Emilie Cordina-duverger, Pascal Guénel, Thérèse Truong, Claire Mulot, Lauren R. Teras, Alpa V. Patel, Laure DossusRudolf Kaaks, Reiner Hoppe, Wing-yee Lo, Thomas Brüning, Ute Hamann, Kamila Czene, Marike Gabrielson, Per Hall, Mikael Eriksson, Audrey Jung, Heiko Becher, Fergus J. Couch, Nicole L. Larson, Janet E. Olson, Kathryn J. Ruddy, Graham G. Giles, Robert J. Macinnis, Melissa C. Southey, Loic Le Marchand, Lynne R. Wilkens, Christopher A. Haiman, Håkan Olsson, Annelie Augustinsson, Ute Krüger, Philippe Wagner, Christopher Scott, Stacey J. Winham, Celine M. Vachon, Charles M. Perou, Andrew F. Olshan, Melissa A. Troester, David J. Hunter, Heather A. Eliassen, Rulla M. Tamimi, Kristen Brantley, Irene L. Andrulis, Jonine Figueroa, Stephen J. Chanock, Thomas U. Ahearn, Montserrat García-closas, Gareth D. Evans, William G. Newman, Elke M. Van Veen, Anthony Howell, Alicja Wolk, Niclas Håkansson, Hoda Anton-culver, Argyrios Ziogas, Michael E. Jones, Nick Orr, Minouk J. Schoemaker, Anthony J. Swerdlow, Cari M. Kitahara, Martha Linet, Ross L. Prentice, Douglas F. Easton, Roger L. Milne, Peter Kraft, Jenny Chang-claude, Sara Lindström

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Breast cancer is one of the most common cancers in women. There were 268,600 new cases and 41,760 deaths due to breast cancer estimated in the U.S. in 2019 1 . The use of menopausal hormone therapy (MHT) is associated with up to 23% increased risk of breast cancer. MHT use has been reduced among postmenopausal women since the report by the Women’s Health Initiative (WHI) clinical trial and observational study 2,3 which has been subsequently confirmed by other studies and meta-analyses 4,5 . Breast cancer risk increases with longer duration of use6, and is higher for combined estrogen–progesterone MHT (EPT) use as compared with estrogen-only (ET) regimens4,5. Additionally, the association between MHT use and breast cancer may also differ by tumor molecular subtype. A prospective cohort study in UK found that current MHT use was associated with increased risk for estrogen receptor positive (ER+) breast cancers, but not with ER- breast cancers 7 . Several other observational
studies also found that MHT use was associated with elevated risk of ER+ breast cancer 8–12 . The biological mechanisms underlying the effect of MHT use on breast cancer risk is not fully understood. One proposed mechanism is that higher estrogen and progesterone levels increase the proliferation of breast
epithelial cells, which results in accumulation of genetic mutations and insufficient DNA repair13,14, and therefore induces mutagenesis 15,16 . Genome-wide association studies (GWAS) have identified over 200 single nucleotide polymorphisms (SNPs) that are associated with invasive breast cancer risk 17–19 . Further analyses based on these GWAS findings have identified several genes that might interact with MHT use on breast cancer risk, including
SNPs regulating the fibroblast growth factor receptor two (FGFR2) gene 20 , as well as SNPs close to the Kruppel like factor 4 (KLF4) gene and the insulin like growth-factor-binding protein 5 (IGFBP5) gene 21–23 . A meta-analysis of four genome-wide case-only interaction studies found suggestive evidence of interactions between MHT use and SNPs in genes related to transmembrane signaling and immune cell activation 24 . However, none of the findings reached genome-wide significance.
In the present study, we performed a comprehensive genome-wide interaction analysis of current MHT use by pooling individual-level data from 26 epidemiological studies. We also performed genome-wide interaction analysis of MHT use on ER+ breast cancer specifically
Original languageEnglish
JournalScientific Reports
Issue number1
Early online date13 Apr 2022
Publication statusE-pub ahead of print - 13 Apr 2022


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