Johnson Nichola, Dudbridge Frank, Orr Nick, Gibson Lorna, Jones Michael E, Schoemaker Minouk J, Folkerd Elizabeth J, Haynes Ben P, Hopper John L, Southey Melissa C, Dite Gillian S, Apicella Carmel, Schmidt Marjanka K, Broeks Annegien, Van't Veer Laura J, Atsma Femke, Muir Kenneth, Lophatananon Artitaya, Fasching Peter A, Beckmann Matthias W, Ekici Arif B, Renner Stefan P, Sawyer Elinor, Tomlinson Ian, Kerin Michael, Miller Nicola, Burwinkel Barbara, Marme Frederik, Schneeweiss Andreas, Sohn Christof, Guénel Pascal, Truong Therese, Cordina Emilie, Menegaux Florence, Bojesen Stig E, Nordestgaard Børge G, Flyger Henrik, Milne Roger, Zamora M Pilar, Arias Perez Jose Ignacio, Benitez Javier, Bernstein Leslie, Anton-Culver Hoda, Ziogas Argyrios, Clarke Dur Christina, Brenner Hermann, Müller Heiko, Arndt Volker, Dieffenbach Aida Karina, Meindl Alfons, Heil Joerg, Bartram Claus R, Schmutzler Rita K, Brauch Hiltrud, Justenhoven Christina, Ko Yon-Dschun, Nevanlinna Heli, Muranen Taru A, Aittomäki Kristiina, Blomqvist Carl, Matsuo Keitaro, Dörk Thilo, Bogdanova Natalia V, Antonenkova Natalia N, Lindblom Annika, Mannermaa Arto, Kataja Vesa, Kosma Veli-Matti, Hartikainen Jaana M, Chenevix-Trench Georgia, Beesley Jonathan, Wu Anna H, Van den Berg David, Tseng Chiu-Chen, Lambrechts Diether, Smeets Dominiek, Neven Patrick, Wildiers Hans, Chang-Claude Jenny, Rudolph Anja, Nickels Stefan, Flesch-Janys Dieter, Radice Paolo, Peterlongo Paolo, Bonanni Bernardo, Pensotti Valeria, Couch Fergus J, Olson Janet E, Wang Xianshu, Fredericksen Zachary, Pankratz Vernon S, Giles Graham G, Severi Gianluca, Baglietto Laura, Haiman Chris, Simard Jacques, Goldberg Mark S, Labrèche France, Dumont Martine, Soucy Penny, Teo Soo, Yip Cheng Har, Phuah Sze Yee, Cornes Belinda K, Kristensen Vessela N, Grenaker Alnæs Grethe, Børresen-Dale Anne-Lise, Zheng Wei, Winqvist Robert, Pylkäs Katri, Jukkola-Vuorinen Arja, Grip Mervi, Andrulis Irene L, Knight Julia A, Glendon Gord, Mulligan Anna Marie, Devillee Peter, Figueroa Jonine, Chanock Stephen J, Lissowska Jolanta, Sherman Mark E, Hall Per, Schoof Nils, Hooning Maartje, Hollestelle Antoinette, Oldenburg Rogier A, Tilanus-Linthorst Madeleine, Liu Jianjun, Cox Angie, Brock Ian W, Reed Malcolm W R, Cross Simon S, Blot William, Signorello Lisa B, Pharoah Paul D P, Dunning Alison M, Shah Mitul, Kang Daehee, Noh Dong-Young, Park Sue K, Choi Ji-Yeob, Hartman Mikael, Miao Hui, Lim Wei Yen, Tang Anthony, Hamann Ute, Försti Asta, Rüdiger Thomas, Ulmer Hans Ulrich, Jakubowska Anna, Lubinski Jan, Jaworska-Bieniek Katarzyna, Durda Katarzyna, Sangrajrang Suleeporn, Gaborieau Valerie, Brennan Paul, McKay James, Slager Susan, Toland Amanda E, Vachon Celine, Yannoukakos Drakoulis, Shen Chen-Yang, Yu Jyh-Cherng, Huang Chiun-Sheng, Hou Ming-Feng, González-Neira Anna, Tessier Daniel C, Vincent Daniel, Bacot Francois, Luccarini Craig, Dennis Joe, Michailidou Kyriaki, Bolla Manjeet K, Wang Jean, Easton Douglas F, García-Closas Montserrat, Dowsett Mitch, Ashworth Alan, Swerdlow Anthony J, Peto Julian, dos Santos Silva Isabel, Fletcher Olivia
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
Division of Breast Cancer Research, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
Breast Cancer Res. 2014 May 26;16(3):R51. doi: 10.1186/bcr3662.
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.
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.
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 (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 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 (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29).
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.
我们之前已经表明，一个位于CYP3A基因座（7q22.1）的标签单核苷酸多态性（rs10235235）与绝经前尿雌酮葡萄糖醛酸水平降低以及年龄≤50岁女性患乳腺癌风险适度降低有关。
我们在一项大型病例对照研究中进一步调查了rs10235235与乳腺癌风险的关联，该研究纳入了来自参与乳腺癌协会联盟的52项研究中的47346例病例和47570例对照。使用定制的Illumina Infinium芯片对rs10235235进行基因分型。进行分层分析以确定这种关联是否因诊断年龄、种族、初潮年龄或肿瘤特征而改变。
我们证实了rs10235235与欧洲血统女性患乳腺癌风险的关联，但没有发现证据表明这种关联因诊断年龄而异。杂合子和纯合子优势比（OR）分别为OR = 0.98（95%CI 0.94, 1.01；P = 0.2）和OR = 0.80（95%CI 0.69, 0.93；P = 0.004）（P趋势 = 0.02）。没有证据表明肿瘤特征会影响这种关联。然而，rs10235235与对照的初潮年龄有关（P趋势 = 0.005），但与病例无关（P趋势 = 0.97）。因此，rs10235235与乳腺癌风险之间的关联因初潮年龄而异（P异质性 = 0.02）；rs10235235的罕见等位基因与初潮年龄≥15岁女性患乳腺癌风险降低有关（OR杂合子 = 0.84，95%CI 0.75, 0.94；OR纯合子 = 0.81，95%CI 0.51, 1.30；P趋势 = 0.002），但与初潮年龄≤11岁女性无关（OR杂合子 = 1.06，95%CI 0.95, 1.19，OR纯合子 = 1.07，95%CI 0.67, 1.72；P趋势 = 0.29）。
据我们所知，rs10235235是第一个与乳腺癌风险和初潮年龄均相关的单核苷酸多态性，这与初潮年龄较晚和乳腺癌风险降低之间有充分记录的关联一致。这些关联可能是通过对循环激素水平的影响介导的。
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