Association of Expression of YTH-Domain Family Protein 3 (YTHDF3) With Brain Metastases and Unfavorable Survival in Patients With Stage IV Lung Adenocarcinoma.

YTH-domain family protein 3 (YTHDF3) is an N6-methyladenosine (m6A) reader that plays important roles in regulating mRNA stability and translation. It can promote tumor proliferation, migration, and invasion; however, little is known about the associations between YTHDF3 expression and brain metastasis (BM) and prognosis in the advanced lung adenocarcinoma (LUAD). Immunohistochemistry (IHC) was performed for YTHDF3 expression in LUAD specimens. The correlations were evaluated between YTHDF3 expression and clinicopathological features. Furthermore, the Kaplan-Meier analysis and Cox proportional hazard model were used to assess effect of YTHDF3 on patient clinical outcomes. There is a strong correlation between YTHDF3 expression and BM in LUAD (r = 0.656, p < 0.001), and the expression of YTHDF3 was significantly higher in patients with BM than in those without BM (66.7% vs. 14.5%, p < 0.001). Moreover, the patients with high YTHDF3 expression had an approximately 12-fold increased risk to have BM compared with those with low YTHDF3 expression (aOR,12.2; 95% CI, 2.4-18.1). Furthermore, the patients with high YTHDF3 expression had worse progression-free survival (PFS) and overall survival (OS) in all patients with stage IV LUAD and those with BM (all log-rank p < 0.001). Multivariable analyzes showed that patients with higher YTHDF3 expression was significantly associated with both worse PFS and OS in all patients with stage IV LUAD (aHR, 2.7, 95% CI, 1.2-5.9 for PFS and aHR, 3.0, 95%CI, 1.8-5.3 for OS) and those with BM (aHR, 2.9, 95%CI, 1.7-4.8 for PFS and aHR, 3.3, 95%CI, 1.6-5.7 for OS). Overexpression of YTHDF3 was significantly associated with BM and poor survival outcomes among patients with LUAD.