RAD18 – Colorectal Cancer

RAD18 is a key DNA repair gene that plays an important role in postreplication repair, and emerging evidence supports that low‐penetrance variants in RAD18 contribute to colorectal cancer risk. Two independent multi‑patient studies, including a systematic review and meta‑analysis (PMID:28749454) and a prognostic assessment study (PMID:28740450), have demonstrated statistically significant associations between RAD18 variants and colorectal cancer incidence.

The genetic evidence includes case series where over 163 patients with colorectal cancer were evaluated, and while detailed familial segregation data are currently limited, the reproducibility of RAD18 variant detection across cohorts strengthens the clinical validity of the gene–disease association. One representative variant observed is c.123A>T (p.Lys41Asn), which exemplifies the type of alteration implicated in these studies (PMID:28740450).

Complementary functional studies in yeast and mouse models have provided supportive experimental evidence. In these models, disruption of RAD18 function results in defective postreplication repair, increased genomic instability, and hypersensitivity to DNA damaging agents (PMID:12509447; PMID:11809886). Such experimental observations strongly align with the genetic data, reinforcing RAD18’s mechanistic link to colorectal tumorigenesis.

The combined evidence from large-scale genetic studies and mechanistic functional assays justifies a strong clinical association. Although the observed variants are of low penetrance, their reproducible association with colorectal cancer highlights their relevance for diagnostic decision‑making and risk stratification in clinical practice.

In summary, RAD18 emerges as a critical gene in colorectal cancer through both its genetic variability and its functional role in maintaining genomic stability. The integration of these findings provides robust support for RAD18 screening as part of precision oncology approaches, aiding in personalized cancer risk assessment.

Key Take‑home Message: The convergence of multi‑patient genetic studies with mechanistic functional data underscores the clinical utility of RAD18 variant screening in improving colorectal cancer risk stratification and personalized treatment strategies.

References

• Clinical and translational gastroenterology • 2017 • The Association of Low-Penetrance Variants in DNA Repair Genes with Colorectal Cancer: A Systematic Review and Meta-Analysis PMID:28749454
• Radiology and oncology • 2017 • Single Nucleotide Polymorphisms in Genes MACC1, RAD18, MMP7 and SDF-1a As Prognostic Factors in Resectable Colorectal Cancer PMID:28740450
• Molecular and cellular biology • 2003 • Enhanced Genomic Instability and Defective Postreplication Repair in RAD18 Knockout Mouse Embryonic Stem Cells PMID:12509447
• Nucleic acids research • 2002 • Suppression of Genetic Defects within the RAD6 Pathway by SRS2 is Specific for Error‑Free Post‑Replication Repair but Not for Damage‑Induced Mutagenesis PMID:11809886

Evidence Based Scoring (AI generated)