Bau Da-Tian, Liu Ting-Yuan, Yang Jai-Sing, Chen William Tzu-Liang, Tsai Chia-Wen, Chang Wen-Shin, Ke Tao-Wei, Liao Chi-Chou, Chen Yu-Chia, Chang Yen-Ting, Tsai Fuu-Jen
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Department of Medical Research, Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan.
Mol Carcinog. 2025 Jan;64(1):25-32. doi: 10.1002/mc.23823. Epub 2024 Oct 11.
We conducted the first genome-wide association study (GWAS) of colorectal cancer (CRC) in Taiwan with 5342 cases and 61,015 controls. Ninety-two SNPs in three genomic regions reached genome-wide significance (p < 5 × 10). The lead SNPs in these three regions were: rs12778523 (OR = 1.18, 95% CI, 1.15-1.23, p = 4.51 × 10), an intergenic SNP between RNA5SP299 and LINC02676 at chromosome 10p14; rs647161 (OR = 1.14, 95% CI, 1.09-1.19, p = 2.21 × 10), an intronic SNP in PITX1 at 5q31.1, and rs10427139 (OR = 1.20, 95% CI, 1.14-1.28, p = 3.62 × 10), an intronic SNP in GPATCH1 at 19q13.1. We further validated CRC susceptibility SNPs previously identified through GWAS in other populations. A total of 61 CRC susceptibility SNPs were confirmed in Taiwanese. The top validated putative CRC susceptibility genes included: POU2AF2, HAO1, LAMC1, EIF3H, BMP2, ZMIZ1, BMP4, POLD3, CDKN1A, PREX1, CDKN2B, CDH1, and LRIG1. The top enriched pathways included TGF-β signaling, BMP signaling, extracellular matrix organization, DNA repair, and cell cycle control. We could not validate SNPs in HLA-G at 6p22.1 and in NOTCH4 at 6p21.32. We generated a weighted genetic risk score (GRS) using the 61 SNPs and constructed receiver operating characteristic (ROC) curves using the GRS to predict CRC. The area under the ROC curve (AUC) was 0.589 for GRS alone and 0.645 for GRS, sex, and age. These susceptibility SNPs and genes provide important insights into the molecular mechanisms of CRC development and help identify high-risk individuals for CRC in Taiwan.
我们在台湾对5342例结直肠癌（CRC）患者和61015名对照进行了首次全基因组关联研究（GWAS）。三个基因组区域中的92个单核苷酸多态性（SNP）达到全基因组显著性水平（p < 5×10⁻⁸）。这三个区域中的主要SNP分别为：rs12778523（比值比[OR]=1.18，95%置信区间[CI]，1.15 - 1.23，p = 4.51×10⁻⁸），位于10号染色体p14上RNA5SP299与LINC02676之间的基因间SNP；rs647161（OR = 1.14，95% CI，1.09 - 1.19，p = 2.21×10⁻⁸），位于5号染色体q31.1上PITX1基因的内含子SNP；以及rs10427139（OR = 1.20，95% CI，1.14 - 1.28，p = 3.62×10⁻⁸），位于19号染色体q13.1上GPATCH1基因的内含子SNP。我们进一步验证了先前在其他人群中通过GWAS鉴定出的CRC易感性SNP。在台湾人群中总共确认了61个CRC易感性SNP。经充分验证的主要CRC易感基因包括：POU2AF2、HAO1、LAMC1、EIF3H、BMP2、ZMIZ1、BMP4、POLD3、CDKN1A、PREX1、CDKN2B、CDH1和LRIG1。主要富集的通路包括转化生长因子-β（TGF-β）信号传导、骨形态发生蛋白（BMP）信号传导、细胞外基质组织、DNA修复和细胞周期调控。我们未能验证位于6号染色体p22.1上HLA - G基因以及位于6号染色体p21.32上NOTCH4基因中的SNP。我们使用这61个SNP生成了加权遗传风险评分（GRS），并使用GRS构建了受试者工作特征（ROC）曲线以预测CRC。仅GRS的ROC曲线下面积（AUC）为0.589，GRS、性别和年龄联合的AUC为0.645。这些易感性SNP和基因有助于深入了解CRC发生发展的分子机制，并有助于识别台湾地区CRC的高危个体。
