Abstract
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 < 0.1 × 10−4). Among the 5 series, the remission rates were higher in patients with USP8-mutated-alleles than in those with the USP8-WT-alleles (p < 0.1 × 10−4).
Conclusion
Our data, as well as the retrospective review of CD series associated with USP8-mutated alleles, show heterogeneous findings among the series. Several drawbacks included the lack of a systematic protocol to evaluate these patients before surgery and follow-up. Further prospective studies using a systematic protocol will provide more consistent information about the influence of the corticotropinomas with USP8-mutated alleles on the phenotype, responses to treatment and outcome of patients with CD.
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Acknowledgements
We thank Prof. Margaret de Castro for providing us with the USP8-mutated control DNA, and we appreciate all the staff of Laboratorio de Investigacao Medica LIM 42; LIM 25 and Histocell Laboratório de Anatomia Patológica. We also thank Mariana Funari and Vinicius Calsavara for the genetic analysis and meta-analysis, respectively.
Funding
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) – Finance Code 001 to IQW.
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The authors declare that have no conflicts of interest.
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This study was approved by the Ethical Committee of the Hospital das Clinicas of the University of Sao Paulo, Brazil (#56235216.0.0000.0068) and the procedures were performed in accordance with the 1964 Helsinki Declaration and its later amendments. The signing of informed consent was required.
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Wanichi, I.Q., de Paula Mariani, B.M., Frassetto, F.P. et al. Cushing’s disease due to somatic USP8 mutations: a systematic review and meta-analysis. Pituitary 22, 435–442 (2019). https://doi.org/10.1007/s11102-019-00973-9
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DOI: https://doi.org/10.1007/s11102-019-00973-9