Wu Chengmi, Zhou Jingyi, Wu Qian, Xu Shu, Jiang Jie, Li Sha, Chen Xuechen
College of Pharmacy, Jinan University, Guangzhou, China.
Department of Oncology, Shenzhen Guangming District People's Hospital, Shenzhen, China.
Cancer Rep (Hoboken). 2025 May;8(5):e70230. doi: 10.1002/cnr2.70230.
Several single nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWASs) on colorectal cancer (CRC) incidence are also shown as promising predictors of clinical outcomes in CRC patients. These genetic variants might help inform precision prognostic strategies by predicting disease progression, treatment response, and overall survival, thereby guiding more personalized treatment plans. However, conflicting evidence exists regarding their clinical relevance.
A systematic review and meta-analysis was performed to assess the potential of GWAS-identified SNPs in predicting CRC outcomes.
We conducted a comprehensive search of PubMed, Web of Science, Embase, and Cochrane databases up to 18 October 2024 for prospective studies that investigated the associations of CRC-related SNPs and polygenic risk scores (PRSs) built based on multiple SNPs with clinical outcomes. Quality of the included studies was assessed using the Newcastle-Ottawa Scale, and the heterogeneity was assessed by I index and Cochran's Q test. The final analysis included 22 studies with overall high quality and heterogeneity in several aspects (e.g., genetic models, ethnic background, and genetic signatures of CRC types). Among over 100 CRC risk-related loci, 12 SNPs were statistically associated with CRC clinical outcomes (mainly survival outcomes), which were replicated in multiple studies. Notably, rs9929218 and rs6983267, located in genes involved in processes of tumorigenesis, were linked to poor survival with hazard ratios (95% CIs) of 1.26 (1.12-1.42) under a recessive model and 1.33 (1.10-1.61) under an additive model, respectively, in the stratified analysis by genetic models. Besides, PRSs built based on survival-related SNPs were moderately associated with overall survival in CRC patients with hazard ratios exceeding 2.6 for each one-point increase in PRS.
Individual genetic variants and PRSs are predictive of CRC survival, and might serve as potential factors for risk stratification, which could help develop personalized treatment and surveillance strategies for CRC patients. However, the potential for false positives and the significant heterogeneity among studies that cannot be fully addressed in the current analysis due to limited data require a cautious interpretation of these findings. Large-scale studies are warranted to further explore and validate GWAS-identified SNPs for promising prognostic biomarkers in CRC patients while accounting for factors such as ethnic differences and tumor subtypes.
通过全基因组关联研究（GWAS）确定的几种单核苷酸多态性（SNP），在结直肠癌（CRC）发病率研究中也被证明是CRC患者临床结局的有前景的预测指标。这些基因变异可能通过预测疾病进展、治疗反应和总生存期，为精准预后策略提供信息，从而指导更个性化的治疗方案。然而，关于它们的临床相关性存在相互矛盾的证据。
进行一项系统综述和荟萃分析，以评估GWAS确定的SNP在预测CRC结局方面的潜力。
我们全面检索了截至2024年10月18日的PubMed、Web of Science、Embase和Cochrane数据库，以查找前瞻性研究，这些研究调查了CRC相关SNP以及基于多个SNP构建的多基因风险评分（PRS）与临床结局的关联。使用纽卡斯尔-渥太华量表评估纳入研究的质量，通过I指数和Cochrane Q检验评估异质性。最终分析纳入了22项总体质量较高且在几个方面存在异质性的研究（例如，遗传模型、种族背景和CRC类型的基因特征）。在100多个CRC风险相关位点中，12个SNP与CRC临床结局（主要是生存结局）存在统计学关联，这些关联在多项研究中得到了重复验证。值得注意的是位于参与肿瘤发生过程的基因中的rs9929218和rs6983267，在按遗传模型进行的分层分析中，在隐性模型下与较差生存相关，风险比（95%CI）为1.26（1.12 - 1.42），在加性模型下风险比为1.33（1.10 - 1.61）。此外，基于与生存相关的SNP构建的PRS与CRC患者的总生存期存在中度关联，PRS每增加1分，风险比超过2.6。
个体基因变异和PRS可预测CRC生存，并可能作为风险分层的潜在因素，这有助于为CRC患者制定个性化的治疗和监测策略。然而，由于数据有限，当前分析中无法完全解决的假阳性可能性和研究之间的显著异质性需要对这些发现进行谨慎解读。有必要开展大规模研究，进一步探索和验证GWAS确定的SNP作为CRC患者有前景的预后生物标志物，同时考虑种族差异和肿瘤亚型等因素。
