Ananth P Abraham1, Rekha Pai2, Daniel L Beno2, Geeta Chacko3, Hesarghatta Shyamasunder Asha4, Simon Rajaratnam4, Nitin Kapoor4, Nihal Thomas4, Ari G Chacko1. 1. Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India. 2. Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India. 3. Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India. geetachacko@cmcvellore.ac.in. 4. Department of Endocrinology, Christian Medical College, Vellore, Tamil Nadu, India.
Abstract
PURPOSE: To estimate the prevalence of USP8, USP48, and BRAF mutations in patients with Cushing's disease (CD) from the Indian subcontinent, and determine their genotype-phenotype correlation. METHODS: We prospectively recruited 46 patients with CD who underwent surgery between September 2015 and July 2019 at our institute. Fresh frozen tumour tissue was obtained in all patients. Using Sanger sequencing, the presence of somatic USP8 mutations was documented and the frequency of USP48 and BRAF mutations in USP8 wild-type corticotroph adenomas was determined. Clinical, hormonal, and surgical data were then compared between USP8-, USP48- and BRAF-variant carriers and patients with wild-type tumours. RESULTS: Signature USP8 mutations were detected in 17 (37%) patients. Of the 29 USP8 wild-type adenomas, 4 (13.8%) harboured USP48 mutations, one of them being a splice-site mutation that has previously not been described. BRAF mutations were not found in any of the 29 patients. Corticotroph adenomas with USP8 mutations had a higher incidence of Crooke's hyaline change than wild-type tumours (70.6 vs. 37.9%, p = 0.032). Adenomas with USP48 mutations had a higher rate of cavernous sinus invasion than their wild-type counterparts (50 vs. 4%, p = 0.042). No other significant phenotypic difference could be established between mutant and wild-type tumours. CONCLUSIONS: The prevalence of USP8 mutations in our series of patients with CD was 37%. The prevalence of USP48 mutations in USP8 wild-type adenomas was 13.8%, including a novel splice-site mutation. BRAF mutations were not found in any USP8 wild-type tumour. USP8-mutants showed significantly more Crooke's hyaline change and USP48-mutants were more likely to demonstrate cavernous sinus invasion.
PURPOSE: To estimate the prevalence of USP8, USP48, and BRAF mutations in patients with Cushing's disease (CD) from the Indian subcontinent, and determine their genotype-phenotype correlation. METHODS: We prospectively recruited 46 patients with CD who underwent surgery between September 2015 and July 2019 at our institute. Fresh frozen tumour tissue was obtained in all patients. Using Sanger sequencing, the presence of somatic USP8 mutations was documented and the frequency of USP48 and BRAF mutations in USP8 wild-type corticotroph adenomas was determined. Clinical, hormonal, and surgical data were then compared between USP8-, USP48- and BRAF-variant carriers and patients with wild-type tumours. RESULTS: Signature USP8 mutations were detected in 17 (37%) patients. Of the 29 USP8 wild-type adenomas, 4 (13.8%) harboured USP48 mutations, one of them being a splice-site mutation that has previously not been described. BRAF mutations were not found in any of the 29 patients. Corticotroph adenomas with USP8 mutations had a higher incidence of Crooke's hyaline change than wild-type tumours (70.6 vs. 37.9%, p = 0.032). Adenomas with USP48 mutations had a higher rate of cavernous sinus invasion than their wild-type counterparts (50 vs. 4%, p = 0.042). No other significant phenotypic difference could be established between mutant and wild-type tumours. CONCLUSIONS: The prevalence of USP8 mutations in our series of patients with CD was 37%. The prevalence of USP48 mutations in USP8 wild-type adenomas was 13.8%, including a novel splice-site mutation. BRAF mutations were not found in any USP8 wild-type tumour. USP8-mutants showed significantly more Crooke's hyaline change and USP48-mutants were more likely to demonstrate cavernous sinus invasion.
Authors: Mathias Riebold; Christian Kozany; Lee Freiburger; Michael Sattler; Michael Buchfelder; Felix Hausch; Günter K Stalla; Marcelo Paez-Pereda Journal: Nat Med Date: 2015-02-09 Impact factor: 53.440
Authors: Martin Reincke; Silviu Sbiera; Akira Hayakawa; Marily Theodoropoulou; Andrea Osswald; Felix Beuschlein; Thomas Meitinger; Emi Mizuno-Yamasaki; Kohei Kawaguchi; Yasushi Saeki; Keiji Tanaka; Thomas Wieland; Elisabeth Graf; Wolfgang Saeger; Cristina L Ronchi; Bruno Allolio; Michael Buchfelder; Tim M Strom; Martin Fassnacht; Masayuki Komada Journal: Nat Genet Date: 2014-12-08 Impact factor: 38.330
Authors: Luis G Perez-Rivas; Marily Theodoropoulou; Francesco Ferraù; Clara Nusser; Kohei Kawaguchi; Constantine A Stratakis; Fabio Rueda Faucz; Luiz E Wildemberg; Guillaume Assié; Rudi Beschorner; Christina Dimopoulou; Michael Buchfelder; Vera Popovic; Christina M Berr; Miklós Tóth; Arif Ibrahim Ardisasmita; Jürgen Honegger; Jerôme Bertherat; Monica R Gadelha; Felix Beuschlein; Günter Stalla; Masayuki Komada; Márta Korbonits; Martin Reincke Journal: J Clin Endocrinol Metab Date: 2015-05-05 Impact factor: 5.958
Authors: Isabel Weigand; Lisanne Knobloch; Jörg Flitsch; Wolfgang Saeger; Camelia M Monoranu; Kerstin Höfner; Sabine Herterich; Roman Rotermund; Cristina L Ronchi; Michael Buchfelder; Markus Glatzel; Christian Hagel; Martin Fassnacht; Timo Deutschbein; Silviu Sbiera Journal: J Clin Endocrinol Metab Date: 2019-07-01 Impact factor: 5.958
Authors: Silviu Sbiera; Luis Gustavo Perez-Rivas; Lyudmyla Taranets; Isabel Weigand; Jörg Flitsch; Elisabeth Graf; Camelia-Maria Monoranu; Wolfgang Saeger; Christian Hagel; Jürgen Honegger; Guillaume Assie; Ad R Hermus; Günter K Stalla; Sabine Herterich; Cristina L Ronchi; Timo Deutschbein; Martin Reincke; Tim M Strom; Nikita Popov; Marily Theodoropoulou; Martin Fassnacht Journal: Neuro Oncol Date: 2019-10-09 Impact factor: 12.300
Authors: Pietro Locantore; Rosa Maria Paragliola; Gianluca Cera; Roberto Novizio; Ettore Maggio; Vittoria Ramunno; Andrea Corsello; Salvatore Maria Corsello Journal: Int J Mol Sci Date: 2022-06-19 Impact factor: 6.208