, Volume 22, Issue 4, pp 435–442 | Cite as

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

  • Ingrid Quevedo Wanichi
  • Beatriz Marinho de Paula Mariani
  • Fernando Pereira Frassetto
  • Sheila Aparecida Coelho Siqueira
  • Nina Rosa de Castro Musolino
  • Malebranche Berardo Carneiro Cunha-Neto
  • Gilberto Ochman
  • Valter Angelo Sperling Cescato
  • Marcio Carlos Machado
  • Ericka Barbosa Trarbach
  • Marcello Delano Bronstein
  • Maria Candida Barisson Villares FragosoEmail author



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.


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).


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).


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.


Microcorticotropinomas Macrocorticotropinomas Ubiquitin specific peptidase 8 Mutations 



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.


This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) – Finance Code 001 to IQW.

Compliance with ethical standards

Conflict of interest

The authors declare that have no conflicts of interest.

Ethical approval

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ingrid Quevedo Wanichi
    • 1
  • Beatriz Marinho de Paula Mariani
    • 1
  • Fernando Pereira Frassetto
    • 2
  • Sheila Aparecida Coelho Siqueira
    • 2
  • Nina Rosa de Castro Musolino
    • 3
  • Malebranche Berardo Carneiro Cunha-Neto
    • 3
  • Gilberto Ochman
    • 3
  • Valter Angelo Sperling Cescato
    • 3
  • Marcio Carlos Machado
    • 4
    • 5
    • 6
  • Ericka Barbosa Trarbach
    • 6
  • Marcello Delano Bronstein
    • 4
    • 6
  • Maria Candida Barisson Villares Fragoso
    • 1
    • 7
    • 8
    Email author
  1. 1.Laboratório de Hormônios e Genética Molecular (LIM/42) do Hospital das Clinicas da Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da, Universidade de São PauloSão PauloBrazil
  2. 2.Departamento de Patologia do Hospital das Clinicas da Faculdade de Medicina da, Universidade de São PauloSão PauloBrazil
  3. 3.Unidade de Neuroendocrinologia da Divisão de Neurocirurgia Funcional, Instituto de Psiquiatria do Hospital das Clinicas da Faculdade de Medicina da Universidade de São PauloSão PauloBrazil
  4. 4.Unidade de Neuroendocrinologia da Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da, Universidade de São PauloSão PauloBrazil
  5. 5.Endocrinology ServiceAC Camargo Cancer CenterSão PauloBrazil
  6. 6.Laboratorio de Endocrinologia Celular e Molecular (LIM/25) do Hospital das Clinicas da Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da, Universidade de São PauloSão PauloBrazil
  7. 7.Unidade de Suprarrenal da Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da, Universidade de São PauloSão PauloBrazil
  8. 8.Clinica de Bases do Instituto do Câncer do Estado de São Paulo, ICESPSão PauloBrazil

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