Ingrid Quevedo Wanichi1, Beatriz Marinho de Paula Mariani1, Fernando Pereira Frassetto2, Sheila Aparecida Coelho Siqueira2, Nina Rosa de Castro Musolino3, Malebranche Berardo Carneiro Cunha-Neto3, Gilberto Ochman3, Valter Angelo Sperling Cescato3, Marcio Carlos Machado4,5,6, Ericka Barbosa Trarbach6, Marcello Delano Bronstein4,6, Maria Candida Barisson Villares Fragoso7,8,9. 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 Paulo, Avenida Dr.Enéas de Carvalho Aguiar, 155 - 2 andar bloco 6, São Paulo, CEP 05403900, Brazil. 2. Departamento de Patologia do Hospital das Clinicas da Faculdade de Medicina da, Universidade de São Paulo, São Paulo, Brazil. 3. Unidade de Neuroendocrinologia da Divisão de Neurocirurgia Funcional, Instituto de Psiquiatria do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 4. Unidade de Neuroendocrinologia da Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da, Universidade de São Paulo, São Paulo, Brazil. 5. Endocrinology Service, AC Camargo Cancer Center, São Paulo, Brazil. 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 Paulo, São Paulo, Brazil. 7. 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 Paulo, Avenida Dr.Enéas de Carvalho Aguiar, 155 - 2 andar bloco 6, São Paulo, CEP 05403900, Brazil. maria.villares@hc.fm.usp.br. 8. Unidade de Suprarrenal da Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da, Universidade de São Paulo, São Paulo, Brazil. maria.villares@hc.fm.usp.br. 9. Clinica de Bases do Instituto do Câncer do Estado de São Paulo, ICESP, São Paulo, Brazil. maria.villares@hc.fm.usp.br.
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.
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.
Entities:
Keywords:
Macrocorticotropinomas; Microcorticotropinomas; Mutations; Ubiquitin specific peptidase 8
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