Purrington Kristen S, Slettedahl Seth, Bolla Manjeet K, Michailidou Kyriaki, Czene Kamila, Nevanlinna Heli, Bojesen Stig E, Andrulis Irene L, Cox Angela, Hall Per, Carpenter Jane, Yannoukakos Drakoulis, Haiman Christopher A, Fasching Peter A, Mannermaa Arto, Winqvist Robert, Brenner Hermann, Lindblom Annika, Chenevix-Trench Georgia, Benitez Javier, Swerdlow Anthony, Kristensen Vessela, Guénel Pascal, Meindl Alfons, Darabi Hatef, Eriksson Mikael, Fagerholm Rainer, Aittomäki Kristiina, Blomqvist Carl, Nordestgaard Børge G, Nielsen Sune F, Flyger Henrik, Wang Xianshu, Olswold Curtis, Olson Janet E, Mulligan Anna Marie, Knight Julia A, Tchatchou Sandrine, Reed Malcolm W R, Cross Simon S, Liu Jianjun, Li Jingmei, Humphreys Keith, Clarke Christine, Scott Rodney, Fostira Florentia, Fountzilas George, Konstantopoulou Irene, Henderson Brian E, Schumacher Fredrick, Le Marchand Loic, Ekici Arif B, Hartmann Arndt, Beckmann Matthias W, Hartikainen Jaana M, Kosma Veli-Matti, Kataja Vesa, Jukkola-Vuorinen Arja, Pylkäs Katri, Kauppila Saila, Dieffenbach Aida Karina, Stegmaier Christa, Arndt Volker, Margolin Sara, Balleine Rosemary, Arias Perez Jose Ignacio, Pilar Zamora M, Menéndez Primitiva, Ashworth Alan, Jones Michael, Orr Nick, Arveux Patrick, Kerbrat Pierre, Truong Thérèse, Bugert Peter, Toland Amanda E, Ambrosone Christine B, Labrèche France, Goldberg Mark S, Dumont Martine, Ziogas Argyrios, Lee Eunjung, Dite Gillian S, Apicella Carmel, Southey Melissa C, Long Jirong, Shrubsole Martha, Deming-Halverson Sandra, Ficarazzi Filomena, Barile Monica, Peterlongo Paolo, Durda Katarzyna, Jaworska-Bieniek Katarzyna, Tollenaar Robert A E M, Seynaeve Caroline, Brüning Thomas, Ko Yon-Dschun, Van Deurzen Carolien H M, Martens John W M, Kriege Mieke, Figueroa Jonine D, Chanock Stephen J, Lissowska Jolanta, Tomlinson Ian, Kerin Michael J, Miller Nicola, Schneeweiss Andreas, Tapper William J, Gerty Susan M, Durcan Lorraine, Mclean Catriona, Milne Roger L, Baglietto Laura, dos Santos Silva Isabel, Fletcher Olivia, Johnson Nichola, Van'T Veer Laura J, Cornelissen Sten, Försti Asta, Torres Diana, Rüdiger Thomas, Rudolph Anja, Flesch-Janys Dieter, Nickels Stefan, Weltens Caroline, Floris Giuseppe, Moisse Matthieu, Dennis Joe, Wang Qin, Dunning Alison M, Shah Mitul, Brown Judith, Simard Jacques, Anton-Culver Hoda, Neuhausen Susan L, Hopper John L, Bogdanova Natalia, Dörk Thilo, Zheng Wei, Radice Paolo, Jakubowska Anna, Lubinski Jan, Devillee Peter, Brauch Hiltrud, Hooning Maartje, García-Closas Montserrat, Sawyer Elinor, Burwinkel Barbara, Marmee Frederick, Eccles Diana M, Giles Graham G, Peto Julian, Schmidt Marjanka, Broeks Annegien, Hamann Ute, Chang-Claude Jenny, Lambrechts Diether, Pharoah Paul D P, Easton Douglas, Pankratz V Shane, Slager Susan, Vachon Celine M, Couch Fergus J
Department of Health Sciences Research, Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, USA.
Department of Health Sciences Research.
Hum Mol Genet. 2014 Nov 15;23(22):6034-46. doi: 10.1093/hmg/ddu300. Epub 2014 Jun 13.
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
有丝分裂指数是组织学分级的一个重要组成部分，在乳腺肿瘤发生过程中具有病因学作用。几项小型候选基因研究报告了有丝分裂基因变异与乳腺癌风险之间的关联。在乳腺癌协会联盟（BCAC）的国际乳腺癌和卵巢癌全基因组关联研究（iCOGS）中（n = 39067例；n = 42106例对照），我们测量了来自194个有丝分裂基因的2156个单核苷酸多态性（SNP）与乳腺癌风险之间的关联，包括总体风险以及按组织学分级的风险。TACC2基因中的SNP [rs17550038：比值比（OR）= 1.24，95%置信区间（CI）1.16 - 1.33，P = 4.2×10⁻¹⁰] 和EIF3H基因中的SNP（rs799890：OR = 1.07，95%CI 1.04 - 1.11，P = 8.7×10⁻⁶）与低级别乳腺癌风险显著相关。在对附近FGFR2基因中的乳腺癌风险SNP进行校正后，TACC2基因的信号仍然存在（rs17550038：OR = 1.15，95%CI 1.07 - 1.23，P = 7.9×10⁻⁵），这表明TACC2是低级别乳腺癌一个新的、全基因组范围内具有显著意义的遗传风险位点。虽然没有单个SNP与高级别疾病相关，但一项通路水平的基因集分析表明，194个有丝分裂基因的变异与高级别乳腺癌风险相关（P = 2.1×10⁻³）。这些观察结果将有助于深入了解有丝分裂缺陷对组织学分级和乳腺癌病因学的影响。
