Evaluating SNP Biomarkers for Treatment Response in Rectal Cancer

A new PRISMA systematic review concludes that current germline single nucleotide polymorphism (SNP) evidence is insufficient to guide neoadjuvant chemoradiotherapy (nCRT) decisions in rectal cancer.

The review pooled data from 32 studies encompassing 4,116 patients and assessed 304 SNPs across 126 genes. Despite the breadth of candidate-gene investigation, no single SNP demonstrated reproducible predictive performance suitable for clinical use.

Many studies were small and heterogeneous. Cohorts mixed retrospective and prospective designs, endpoints varied (for example, pathologic complete response versus multiple tumor regression grade scales), genotyping platforms differed, and statistical models often lacked consistent correction for multiple comparisons. These methodological inconsistencies, together with limited sample sizes, likely explain the failure to replicate positive findings across independent cohorts.

Only two SNPs produced repeat signals in more than one study: XRCC1 rs25487 and MTHFR rs1801133. However, the direction and genotype-model associations varied by cohort, and neither variant validated consistently across independent populations. Overall, the cumulative evidence favored null or inconsistent results for most tested SNPs.

Key contributors to these negative findings include underpowered sample sizes that yield unstable effect estimates, inconsistent phenotyping of treatment response, and population stratification with limited ethnic diversity. Selective reporting, publication bias, and a general lack of multi-cohort validation further weaken the evidence base.

Most investigations used single-candidate–SNP strategies that do not capture polygenic architecture or interactions with tumor somatic features and treatment variables.

Key Takeaways:

• The PRISMA review found no individual SNP with consistent predictive value for nCRT response in rectal cancer.
• Out of 304 SNPs across 126 genes, only two (XRCC1 rs25487 and MTHFR rs1801133) showed repeat signals; neither validated reliably.
• Methodological heterogeneity and small samples likely explain inconsistent replication; polygenic and multi-omic strategies are the next step.