Risk of Colorectal Neoplasia in First-Degree Relatives of Colorectal Advanced Adenoma Patients: A Systematic Review.

Abstract

Introduction: Colorectal advanced adenomas (CAAs) are key colorectal cancer (CRC) precursors. Although familial CRC risk is well-established, the neoplastic risk (adenoma, CAA, CRC) in first-degree relative (FDR) of CAA patients is unclear. This systematic review aimed to quantify this risk and identify risk-modifying factors.

Methods: Per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we systematically searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) through May 2025 for observational studies comparing neoplasm risk in FDRs of CAA probands versus controls. Two reviewers independently extracted data and assessed bias (Newcastle-Ottawa Scale). A qualitative synthesis was performed because of heterogeneity.

Results: Of 421 records identified, 4 studies from diverse populations were included. FDRs of CAA patients had a significantly increased risk for any adenoma (odds ratio [OR]/relative risk [RR] 1.33-3.29, with 95% confidence interval [CI] ranging from 0.96 to 5.03) and advanced neoplasia (CAA/CRC) (OR/RR 1.65-6.33, 95% CIs 1.01-43.8). CRC risk findings were inconsistent; 2 larger studies showed a modest risk increase (OR/RR 1.7-2.3, 95% CIs 1.01-5.09), whereas 2 smaller studies reported nonsignificant results. Proband age younger than 60 years, adenoma multiplicity, and male sex of the FDR emerged as potential risk modifiers in individual studies, although evidence is limited. Regarding proband adenoma location, a distal lesion was more consistently associated with increased familial risk, although an association with proximal lesions was also reported.

Discussion: FDRs of CAA patients seem to have an elevated risk of colorectal adenomas, particularly CAAs, although evidence certainty is limited. Documented family history of CAA may warrant consideration as 1 of several factors in future risk-stratified screening approaches; however, the current evidence is insufficient to define CAA-specific screening intervals beyond existing guideline frameworks. Further research is needed to validate risk estimates and optimize screening strategies.