Cushing’s disease due to somatic USP8 mutations: a systematic review and meta-analysis

Purpose Cushing’s disease (CD) is a severe illness generally caused by microcorticotropinomas (MICs) and in approximately 7–20% of patients by macrocorticotropinomas (MACs). USP8 -mutations have been identified as a major genetic cause of CD (~ 50%). Few studies have reported the distribution between MICs–MACs related to USP8 -mutations and their genotype–phenotype correlations. Therefore, we aimed to evaluate USP8 -mutations in a cohort of MICs–MACs from a unique center and to perform a systematic review and meta-analysis. Methods DNA-tumor-tissues from 47 corticotropinomas (16 MICs and 31 MACs) were sequenced. Clinical-biochemical data, radiological imaging data and remission/recurrence rates were evaluated. In addition, we performed a meta-analysis of nine published series (n = 630). Results We identified four different USP8 -mutations previously described, in 11 out of 47 (23.4%) corticotropinomas; 8 out of 11 were MACs. The urinary cortisol levels of our patients with corticotrophin USP8 -mutated-alleles were lower than those of patients with wild-type (WT) alleles ( p ≤ 0.017). The frequency of USP8 -mutated-alleles among the series was approximately 30% with a higher prevalence in female-patients ( p