Abstract
BACKGROUND: The objective of this study was to determine whether lower expression levels of DICER1 are associated with disease recurrence in patients with endometrioid endometrial cancer. The authors also explored DNA methylation and haploinsufficiency as potential mechanisms related to altered DICER1 expression in these tumors. METHODS: DICER1 expression was assessed by quantitative polymerase chain reaction in a selected cohort of endometrioid endometrial tumors (N = 169). Loss of heterozygosity analyses were conducted using 2 single nucleotide polymorphisms, and combined bisulfate restriction analysis was used to assess methylation in the 5'-untranslated region of DICER1 in representative tumors. The correlations between DICER1 expression and clinicopathologic variables, including overall survival (OS) and disease-free survival (DFS), were assessed using nonparametric rank-sum tests and Cox proportional hazard models as appropriate. Survival distributions were described using the Kaplan-Meier method. A nested case-control analysis was conducted to confirm the association between transcript levels and disease recurrence. RESULTS: Lower DICER1 expression (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.05-1.75; P = .02) and advanced disease stage (HR, 2.79; 95%CI, 1.59-4.90; P < .001) were associated with worse DFS. Three variables were associated significantly with reduced OS: age (HR, 1.04; 95%CI, 1.02-1.06; P < .0001), advanced disease stage (HR, 6.41; 95%CI, 3.57-11.52; P < .0001), and high tumor grade (HR, 2.96; 95%CI, 1.46-5.99; P = .003). Nested case-control analyses confirmed that there were lower DICER1 transcript levels in patients who had recurrent disease (P = .01). Deletion of DICER1 sequences was an infrequent event (5% of analyzed patients), and no methylation was observed in the 5' DICER1 regulatory region. CONCLUSIONS: Lower DICER1 transcript levels were correlated with disease recurrence and worse DFS survival in patients with endometrioid endometrial cancer. The factors that influence DICER1 transcript levels in primary endometrial cancers remain unknown.