Li Bin, Wu Mei, Geng Hui, Li Yan, Chen Zhirui, Lu Zequn, Chen Xu, Wang Qiuhong, Song Shuxin, Li Xiangpan, Zhu Xu, Wei Yongchang, Zhu Ying, Miao Xiaoping, Tian Jianbo, Liu Jiuyang, Huang Chaoqun, Yang Xiaojun
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, 115 Donghu Road, Wuchang District, Wuhan, 430071, China.
Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, 115 Donghu Road, Wuchang District, Wuhan, 430071, China.
Carcinogenesis. 2025 Jan 20;46(1). doi: 10.1093/carcin/bgae078.
Although genome-wide association studies have identified dozens of loci associated with colorectal cancer (CRC) susceptibility, the causal genes or risk variants within these loci and their biological functions often remain elusive. Recently, the genomic locus 12p13.32, with the tag single-nucleotide polymorphism rs10774214, was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here, we applied a high-throughput RNA interference approach in CRC cell lines to interrogate the function of genes in this genomic region. Multiple genes were found to affect cell functions, with CCND2 having the most significant effect as an oncogene. Moreover, overexpressed CCND2 could promote CRC cell proliferation. Subsequently, by integrating a fine-mapping analysis and multi-ancestry large-scale population cohorts consisting of 14 358 CRC cases and 34 251 healthy controls, we identified a regulatory variant rs4477507-T that contributed to an increased CRC risk in populations from China (odds ratio = 1.16, 95% confidence interval = 1.11-1.22, P = 4.45 × 10-10) and Europe (odds ratio = 1.17, 95% confidence interval = 1.12-1.21, P = 1.65 × 10-14). Functional characterization of the variant demonstrated that it could act as an allele-specific enhancer to distally facilitate the expression of CCND2 mediated by the transcription factor TEAD4. Overall, our study underscores the essential role of CCND2 in CRC development and delineates its regulatory mechanism mediated by rs4477507, establishing an epidemiological and biological link between genetic variation and CRC pathogenesis.
尽管全基因组关联研究已经确定了数十个与结直肠癌（CRC）易感性相关的基因座，但这些基因座内的因果基因或风险变异及其生物学功能往往仍不清楚。最近，基因组位点12p13.32及其标签单核苷酸多态性rs10774214被确定为亚洲人群中一个关键的CRC风险位点。然而，该区域的功能机制尚未完全阐明。在此，我们在CRC细胞系中应用高通量RNA干扰方法来探究该基因组区域中基因的功能。发现多个基因会影响细胞功能，其中CCND2作为癌基因的影响最为显著。此外，过表达的CCND2可促进CRC细胞增殖。随后，通过整合精细定位分析以及由14358例CRC病例和34251例健康对照组成的多祖先大规模人群队列，我们确定了一个调控变异rs4477507-T，它导致中国人群（优势比=1.16，95%置信区间=1.11-1.22，P=4.45×10-10）和欧洲人群（优势比=1.17，95%置信区间=1.12-1.21，P=1.65×10-14）患CRC的风险增加。该变异的功能表征表明，它可作为等位基因特异性增强子，在远端促进由转录因子TEAD4介导的CCND2表达。总体而言，我们的研究强调了CCND2在CRC发生发展中的重要作用，并阐明了其由rs4477507介导的调控机制，在遗传变异与CRC发病机制之间建立了流行病学和生物学联系。
