Higher TFF1 Expression Linked to Lower Bilateral Retinoblastoma Risk

PURPOSE: This study aims to evaluate the potential of Trefoil Family Factor 1 (TFF1) as a biomarker for the diagnosis and prognosis of retinoblastoma. METHODS: Our protocol was prospectively registered on PROSPERO (CRD420251126954). On July 08, 2025, we conducted a comprehensive literature search across PubMed, Scopus, Web of Science, Embase, Cochrane, and Google Scholar. We included all studies that measured TFF1 expression in retinoblastoma patients and assessed its potential as a biomarker for disease severity. The primary outcomes were laterality, sex, and age at diagnosis. Secondary outcomes included tumor invasion and disease staging. Statistical analysis was performed using RStudio. A random-effects model was used for the analysis, and heterogeneity was assessed using the I². The risk of bias for the included studies was evaluated using the Newcastle-Ottawa Scale for Retrospective cohort studies, while the NIH Quality Assessment Tool for Case Series Studies was used for case series studies. RESULTS: Of the 152 articles initially identified, only 5 met the inclusion criteria, comprising a total of 521 patients with retinoblastoma. Patients with higher TFF1 expression exhibited a significantly lower risk of bilateral involvement (RR = 0.57; 95% CI: 0.39, 0.84; p = 0.0041) and a significantly higher association with being diagnosed after the age of 3 years (RR = 4.26; 95% CI: 1.33, 13.64; p = 0.01). No statistically significant associations were observed with sex (RR = 0.89; 95% CI: 0.74,1.07; p = 0.2), choroid invasion (RR = 0.99; 95% CI: 0.9,1.08; p = 0.76) or optic nerve invasion including no invasion (RR = 0.75; 95% CI: 0.47,1.21; p = 0.24), pre-laminar invasion (RR = 1.13; 95% CI: 0.75,1.7; p = 0.55) or post laminar invasion (RR = 1.04; 95% CI: 0.89,1.21; p = 0.61). CONCLUSION: Retinoblastoma tumors with higher TFF1 expression were associated with a reduced risk of bilateral involvement and an increased likelihood of diagnosis after the age of 3 years. Although the associations with choroidal and optic nerve invasion were not statistically significant, TFF1 remains a promising candidate biomarker for the diagnosis and prognosis of retinoblastoma, particularly due to its absence in normal ocular tissue. Further high-quality studies are required to validate the clinical utility of TFF1 as a reliable diagnostic and prognostic marker in retinoblastoma.