Kabisch Maria, Lorenzo Bermejo Justo, Dünnebier Thomas, Ying Shibo, Michailidou Kyriaki, Bolla Manjeet K, Wang Qin, Dennis Joe, Shah Mitul, Perkins Barbara J, Czene Kamila, Darabi Hatef, Eriksson Mikael, Bojesen Stig E, Nordestgaard Børge G, Nielsen Sune F, Flyger Henrik, Lambrechts Diether, Neven Patrick, Peeters Stephanie, Weltens Caroline, Couch Fergus J, Olson Janet E, Wang Xianshu, Purrington Kristen, Chang-Claude Jenny, Rudolph Anja, Seibold Petra, Flesch-Janys Dieter, Peto Julian, dos-Santos-Silva Isabel, Johnson Nichola, Fletcher Olivia, Nevanlinna Heli, Muranen Taru A, Aittomäki Kristiina, Blomqvist Carl, Schmidt Marjanka K, Broeks Annegien, Cornelissen Sten, Hogervorst Frans B L, Li Jingmei, Brand Judith S, Humphreys Keith, Guénel Pascal, Truong Thérèse, Menegaux Florence, Sanchez Marie, Burwinkel Barbara, Marmé Frederik, Yang Rongxi, Bugert Peter, González-Neira Anna, Benitez Javier, Pilar Zamora M, Arias Perez Jose I, Cox Angela, Cross Simon S, Reed Malcolm W R, Andrulis Irene L, Knight Julia A, Glendon Gord, Tchatchou Sandrine, Sawyer Elinor J, Tomlinson Ian, Kerin Michael J, Miller Nicola, Haiman Christopher A, Schumacher Fredrick, Henderson Brian E, Le Marchand Loic, Lindblom Annika, Margolin Sara, Hooning Maartje J, Hollestelle Antoinette, Kriege Mieke, Koppert Linetta B, Hopper John L, Southey Melissa C, Tsimiklis Helen, Apicella Carmel, Slettedahl Seth, Toland Amanda E, Vachon Celine, Yannoukakos Drakoulis, Giles Graham G, Milne Roger L, McLean Catriona, Fasching Peter A, Ruebner Matthias, Ekici Arif B, Beckmann Matthias W, Brenner Hermann, Dieffenbach Aida K, Arndt Volker, Stegmaier Christa, Ashworth Alan, Orr Nicholas, Schoemaker Minouk J, Swerdlow Anthony, García-Closas Montserrat, Figueroa Jonine, Chanock Stephen J, Lissowska Jolanta, Goldberg Mark S, Labrèche France, Dumont Martine, Winqvist Robert, Pylkäs Katri, Jukkola-Vuorinen Arja, Grip Mervi, Brauch Hiltrud, Brüning Thomas, Ko Yon-Dschun, Radice Paolo, Peterlongo Paolo, Scuvera Giulietta, Fortuzzi Stefano, Bogdanova Natalia, Dörk Thilo, Mannermaa Arto, Kataja Vesa, Kosma Veli-Matti, Hartikainen Jaana M, Devilee Peter, Tollenaar Robert A E M, Seynaeve Caroline, Van Asperen Christi J, Jakubowska Anna, Lubinski Jan, Jaworska-Bieniek Katarzyna, Durda Katarzyna, Zheng Wei, Shrubsole Martha J, Cai Qiuyin, Torres Diana, Anton-Culver Hoda, Kristensen Vessela, Bacot François, Tessier Daniel C, Vincent Daniel, Luccarini Craig, Baynes Caroline, Ahmed Shahana, Maranian Mel, Simard Jacques, Chenevix-Trench Georgia, Hall Per, Pharoah Paul D P, Dunning Alison M, Easton Douglas F, Hamann Ute
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Institute of Medical Biometry and Informatics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Carcinogenesis. 2015 Feb;36(2):256-71. doi: 10.1093/carcin/bgu326. Epub 2015 Jan 13.
The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.
染色体乘客复合体（CPC）在细胞分裂调控中起关键作用。因此，遗传性CPC变异可能影响肿瘤发展。目前的候选基因方法研究了编码关键CPC成分的基因中的单核苷酸多态性（SNP）与乳腺癌风险之间的关系。在乳腺癌协会联盟的39项病例对照研究中的88911名欧洲女性中，对4个CPC基因（INCENP、AURKB、BIRC5和CDCA8）中的15个SNP进行了基因分型。在固定效应荟萃分析中研究了可能的关联。INCENP外显子7中的同义SNP rs1675126与总体乳腺癌风险相关[每A等位基因优势比（OR）为0.95，95%置信区间（CI）为0.92 - 0.98，P = 0.007]，尤其与雌激素受体（ER）阴性乳腺癌肿瘤相关（每A等位基因OR为0.89，95% CI为0.83 - 0.95，P = 0.0005）。未直接进行基因分型的SNP根据千人基因组计划进行推断。INCENP的3'非翻译区的SNP rs1047739和下游的rs144045115显示出与总体（每T等位基因OR为1.03，95% CI为1.00 - 1.06，P = 0.0009）和ER阴性乳腺癌风险（每A等位基因OR为1.06，95% CI为1.02 - 1.10，P = 0.0002）最强的关联信号。BIRC5中的两个基因分型SNP与家族性乳腺癌风险相关（顶级SNP rs2071214：每G等位基因OR为1.12，95% CI为1.04 - 1.21，P = 0.002）。数据表明，CPC途径中的INCENP在欧洲人群中导致ER阴性乳腺癌易感性。尽管CPC遗传变异对散发性和家族性乳腺癌的总负担贡献不大，但其作为乳腺癌治疗新靶点的潜力仍应进一步研究。
