Fu Yi-Ping, Kohaar Indu, Moore Lee E, Lenz Petra, Figueroa Jonine D, Tang Wei, Porter-Gill Patricia, Chatterjee Nilanjan, Scott-Johnson Alexandra, Garcia-Closas Montserrat, Muchmore Brian, Baris Dalsu, Paquin Ashley, Ylaya Kris, Schwenn Molly, Apolo Andrea B, Karagas Margaret R, Tarway McAnthony, Johnson Alison, Mumy Adam, Schned Alan, Guedez Liliana, Jones Michael A, Kida Masatoshi, Hosain G M Monawar, Malats Nuria, Kogevinas Manolis, Tardon Adonina, Serra Consol, Carrato Alfredo, Garcia-Closas Reina, Lloreta Josep, Wu Xifeng, Purdue Mark, Andriole Gerald L, Grubb Robert L, Black Amanda, Landi Maria T, Caporaso Neil E, Vineis Paolo, Siddiq Afshan, Bueno-de-Mesquita H Bas, Trichopoulos Dimitrios, Ljungberg Börje, Severi Gianluca, Weiderpass Elisabete, Krogh Vittorio, Dorronsoro Miren, Travis Ruth C, Tjønneland Anne, Brennan Paul, Chang-Claude Jenny, Riboli Elio, Prescott Jennifer, Chen Constance, De Vivo Immaculata, Govannucci Edward, Hunter David, Kraft Peter, Lindstrom Sara, Gapstur Susan M, Jacobs Eric J, Diver W Ryan, Albanes Demetrius, Weinstein Stephanie J, Virtamo Jarmo, Kooperberg Charles, Hohensee Chancellor, Rodabough Rebecca J, Cortessis Victoria K, Conti David V, Gago-Dominguez Manuela, Stern Mariana C, Pike Malcolm C, Van Den Berg David, Yuan Jian-Min, Haiman Christopher A, Cussenot Olivier, Cancel-Tassin Geraldine, Roupret Morgan, Comperat Eva, Porru Stefano, Carta Angela, Pavanello Sofia, Arici Cecilia, Mastrangelo Giuseppe, Grossman H Barton, Wang Zhaoming, Deng Xiang, Chung Charles C, Hutchinson Amy, Burdette Laurie, Wheeler William, Fraumeni Joseph, Chanock Stephen J, Hewitt Stephen M, Silverman Debra T, Rothman Nathaniel, Prokunina-Olsson Ludmila
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Cancer Res. 2014 Oct 15;74(20):5808-18. doi: 10.1158/0008-5472.CAN-14-1531.
A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
一项膀胱癌全基因组关联研究（GWAS）确定19q12区域内的一个遗传标记rs8102137是一种新的易感变异。该标记位于CCNE1基因上游，CCNE1基因编码细胞周期蛋白E。我们利用两项膀胱癌GWAS的数据（5942例病例和10857例对照）对CCNE1区域进行了遗传精细定位分析。我们发现最初的GWAS标记rs8102137代表一组47个连锁的单核苷酸多态性（SNP）（r²≥0.7），与膀胱癌风险增加相关。从该组中，我们选择了一个功能性启动子变异rs7257330，它在多个细胞系中显示出核蛋白的强等位基因特异性结合。在两项GWAS中，rs7257330仅与侵袭性膀胱癌相关，合并的每个等位基因的比值比（OR）=1.18 [95%置信区间（CI），1.09 - 1.27，P = 4.67×10⁻⁵]，而非侵袭性疾病的OR = 1.01（95% CI，0.93 - 1.10，P = 0.79），病例对照分析的P = 0.0015。在265例膀胱肿瘤中分析的细胞周期蛋白E蛋白表达在侵袭性肿瘤中增加（P = 0.013），并且独立地，与每个rs7257330 - A风险等位基因相关（P趋势 = 0.024）。细胞系中重组细胞周期蛋白E的过表达导致细胞周期显著加速。总之，我们将19q12信号定义为第一个针对侵袭性膀胱癌的GWAS信号。这种遗传关联的分子机制可能与CCNE1风险变异携带者中细胞周期蛋白E的过表达和细胞周期改变有关。结合已确定的膀胱癌风险因素以及其他体细胞和种系遗传标记，CCNE1变异可能有助于纳入膀胱癌风险预测模型。
