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.

Keywords: USP8; ACTH; Cushing's disease; cortisol corticotroph tumour; genetic variant; meta-analysis.