Colorectal Cancer Risk Loci: Prognostic Factors for Clinical Outcomes? A Systematic Review and Meta-Analysis

Background

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.

Aim

A systematic review and meta-analysis was performed to assess the potential of GWAS-identified SNPs in predicting CRC outcomes.

Methods and Results

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 I² 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.

Conclusions

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.