Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study

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Nichola Johnson, Frank Dudbridge, Nick Orr, Lorna Gibson, Michael E Jones, Minouk J Schoemaker, Elizabeth J Folkerd, Ben P Haynes, John L Hopper, Melissa C Southey, Gillian S Dite, Carmel Apicella, Marjanka K Schmidt, Annegien Broeks, Laura J Van T Veer, Femke Atsma, Kenneth Muir, Artitaya Lophatananon, Peter A Fasching, Matthias W Beckmann & 162 others Arif B Ekici, Stefan P Renner, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Pascal Guénel, Therese Truong, Emilie Cordina, Florence Menegaux, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Roger Milne, M Pilar Zamora, Jose Ignacio Arias Perez, Javier Benitez, Leslie Bernstein, Hoda Anton-Culver, Argyrios Ziogas, Christina Clarke Dur, Hermann Brenner, Heiko Müller, Volker Arndt, Aida Karina Dieffenbach, Alfons Meindl, Joerg Heil, Claus R Bartram, Rita K Schmutzler, Hiltrud Brauch, Christina Justenhoven, Yon-Dschun Ko, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Annika Lindblom, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, Jonathan Beesley, Anna H Wu, David Van den Berg, Chiu-Chen Tseng, Diether Lambrechts, Dominiek Smeets, Patrick Neven, Hans Wildiers, Jenny Chang-Claude, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Valeria Pensotti, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Vernon S Pankratz, Graham G Giles, Gianluca Severi, Laura Baglietto, Chris Haiman, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Penny Soucy, Soo Teo, Cheng Har Yip, Sze Yee Phuah, Belinda K Cornes, Vessela N Kristensen, Grethe Grenaker Alnæs, Anne-Lise Børresen-Dale, Wei Zheng, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Jonine Figueroa, Stephen J Chanock, Jolanta Lissowska, Mark E Sherman, Per Hall, Nils Schoof, Maartje Hooning, Antoinette Hollestelle, Rogier A Oldenburg, Madeleine Tilanus-Linthorst, Jianjun Liu, Angie Cox, Ian W Brock, Malcolm Wr Reed, Simon S Cross, William Blot, Lisa B Signorello, Paul Dp Pharoah, Alison M Dunning, Mitul Shah, Daehee Kang, Dong-Young Noh, Sue K Park, Ji-Yeob Choi, Mikael Hartman, Hui Miao, Wei Yen Lim, Anthony Tang, Ute Hamann, Asta Försti, Thomas Rüdiger, Hans Ulrich Ulmer, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Susan Slager, Amanda E Toland, Celine Vachon, Drakoulis Yannoukakos, Chen-Yang Shen, Jyh-Cherng Yu, Chiun-Sheng Huang, Ming-Feng Hou, Anna González-Neira, Daniel C Tessier, Daniel Vincent, Francois Bacot, Craig Luccarini, Joe Dennis, Kyriaki Michailidou, Manjeet K Bolla, Jean Wang, Douglas F Easton, Montserrat García-Closas, Mitch Dowsett, Alan Ashworth, Anthony J Swerdlow, Julian Peto, Isabel Dos Santos Silva, Olivia Fletcher

INTRODUCTION: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age <=50 years.

METHODS: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.

RESULTS: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age >=15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age <=11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29).

CONCLUSIONS: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

Original languageEnglish
JournalBreast cancer research : BCR
Volume16
Issue number3
Pages (from-to)R51
ISSN1465-5411
DOIs
Publication statusPublished - 2014

ID: 138311483