Prevalence and clinical associations of USP8 variants in corticotroph tumours: A systematic review and aggregate data meta-analysis of 2171 cases

Abstract

Objective Somatic USP8 variants are common in corticotroph tumours, but their reported prevalence and association with clinical characteristics vary widely among publications. Aim To determine the prevalence and clinical relevance of USP8 variants based on published evidence. Design and methods We conducted a systematic review and meta-analysis of existing literature. We used PubMed, Embase, and Web of Science databases. The inclusion criteria were original studies including ≥5 patients with Cushing's disease reporting genetic USP8 status. The exclusion criteria were no human research, unclear USP8 information, and case reports (<5 patients). A random-effects model meta-analysis and meta-regression were conducted. Studies reporting functional corticotroph tumours and also silent/non-functioning tumours were not excluded. Results From 6782 extracted records, 44 studies summarizing 51 records were included in our meta-analysis (total n = 2171 cases, 692 with USP8 variants). Pooled prevalence was 31.1% (95% CI, 26.5%-36.0%) and was higher in cases with functional tumours (34.1%; 95% CI, 29.4%-39.1%). Patients with USP8 variants were mostly female (odds ratios [OR] 4.52, 95% CI, 3.39-6.02) and in average 4.47 years younger at diagnosis (95% CI, 2.28-6.65 years younger). USP8 status was associated with higher odds for postoperative remission (OR 1.76, 95% CI, 1.18-2.63) and recurrence (OR 2.38, 95% CI, 1.03-5.48). There was no clear evidence of association with any other clinical or tumour variable included in our analysis, mostly due to heterogeneity among studies. Meta-regression analysis showed that the variability in the prevalence of USP8 variants among studies was related to female/male ratio (adjusted R2 = 0.301), but not to other variables, such as tumour size or invasion. Conclusions The present meta-analysis shows that patients with USP8 variant tumours are mostly female, diagnosed at younger age, more likely to achieve postoperative remission, but at a higher risk of recurrence than those with tumours carrying the reference allele.