Mesa-Eguiagaray Ines, Iakovliev Andrii, Li Xue, Timofeeva Maria, He Yazhou, Zhang Xiaomeng, Din Farhat V N, Farrington Susan M, Spiliopoulou Athina, Dunlop Malcolm G, Theodoratou Evropi
Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Br J Cancer. 2025 Jun 12. doi: 10.1038/s41416-025-03064-8.
Epigenetic changes contribute to colorectal cancer (CRC) pathogenesis. We investigated whether methylation quantitative trait loci (mQTLs) are associated with CRC risk, survival and recurrence.
Using a well-characterised Scottish case-control study (6821 CRC cases, 14,692 controls), we derived 118,982 mQTLs based on the Genetics of DNA Methylation Consortium (GoDMC). Association analysis between mQTLs and CRC risk, survival and recurrence was performed using logistic regression or Cox models respectively. Additionally, colocalisation analysis was performed.
19 mQTLs within 10 distinct genomic regions were associated with CRC risk. Two novel regions were mapped to MDGA2 (p value = ) and STARD3 (p value = ). Four regions mapped to POU5F1B, POU2AF2 (c11orf53)/POU2AF3 (COLCA2), GREM1 and CABLES2 were previously identified. Four regions mapped to PPA2, PANDAR/LAP3P2, POU6F1 and CTIF contained SNPs previously identified by CRC GWAS but with SNPs annotated to different genes. We found no evidence that any of the 19 mQTLs associated with CRC risk influenced survival or recurrence after FDR correction. Colocalisation analysis suggested that in three of the ten regions the causal variants were shared for methylation and CRC risk.
This study adds to the repertoire of CRC genes. However, we found no associations between methylation and CRC survival or recurrence.
表观遗传变化促成了结直肠癌（CRC）的发病机制。我们研究了甲基化数量性状位点（mQTLs）是否与CRC风险、生存率和复发相关。
利用一项特征明确的苏格兰病例对照研究（6821例CRC病例，14,692例对照），我们基于DNA甲基化遗传学联盟（GoDMC）得出了118,982个mQTLs。分别使用逻辑回归或Cox模型对mQTLs与CRC风险、生存率和复发之间进行关联分析。此外，还进行了共定位分析。
10个不同基因组区域内的19个mQTLs与CRC风险相关。两个新区域被定位到MDGA2（p值 = ）和STARD3（p值 = ）。四个区域被定位到POU5F1B、POU2AF2（c11orf53）/POU2AF3（COLCA2）、GREM1和CABLES2，这些区域先前已被鉴定。四个区域被定位到PPA2、PANDAR/LAP3P2、POU6F1和CTIF，其中包含先前通过CRC全基因组关联研究（GWAS）鉴定的单核苷酸多态性（SNPs），但这些SNPs被注释到不同的基因。在错误发现率（FDR）校正后，我们没有发现证据表明与CRC风险相关的19个mQTLs中的任何一个会影响生存率或复发。共定位分析表明，在十个区域中的三个区域，甲基化和CRC风险的因果变异是共享的。
本研究增加了CRC相关基因的种类。然而，我们没有发现甲基化与CRC生存率或复发之间存在关联。
