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Driver mutations in USP8 wild type Cushing's disease

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Driver mutations in USP8 wild type Cushing's disease. / Sbiera, Silviu; Perez-Rivas, Luis Gustavo; Taranets, Lyudmyla; Weigand, Isabel; Flitsch, Jörg; Graf, Elisabeth; Monoranu, Camelia-Maria; Saeger, Wolfgang; Hagel, Christian; Honegger, Jürgen; Assie, Guillaume; Hermus, Ad R; Stalla, Günter K; Herterich, Sabine; Ronchi, Cristina L; Deutschbein, Timo; Reincke, Martin; Strom, Tim M; Popov, Nikita; Theodoropoulou, Marily; Fassnacht, Martin.

In: NEURO-ONCOLOGY, Vol. 21, No. 10, 09.10.2019, p. 1273-1283.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sbiera, S, Perez-Rivas, LG, Taranets, L, Weigand, I, Flitsch, J, Graf, E, Monoranu, C-M, Saeger, W, Hagel, C, Honegger, J, Assie, G, Hermus, AR, Stalla, GK, Herterich, S, Ronchi, CL, Deutschbein, T, Reincke, M, Strom, TM, Popov, N, Theodoropoulou, M & Fassnacht, M 2019, 'Driver mutations in USP8 wild type Cushing's disease', NEURO-ONCOLOGY, vol. 21, no. 10, pp. 1273-1283. https://doi.org/10.1093/neuonc/noz109

APA

Sbiera, S., Perez-Rivas, L. G., Taranets, L., Weigand, I., Flitsch, J., Graf, E., Monoranu, C-M., Saeger, W., Hagel, C., Honegger, J., Assie, G., Hermus, A. R., Stalla, G. K., Herterich, S., Ronchi, C. L., Deutschbein, T., Reincke, M., Strom, T. M., Popov, N., ... Fassnacht, M. (2019). Driver mutations in USP8 wild type Cushing's disease. NEURO-ONCOLOGY, 21(10), 1273-1283. https://doi.org/10.1093/neuonc/noz109

Vancouver

Sbiera S, Perez-Rivas LG, Taranets L, Weigand I, Flitsch J, Graf E et al. Driver mutations in USP8 wild type Cushing's disease. NEURO-ONCOLOGY. 2019 Oct 9;21(10):1273-1283. https://doi.org/10.1093/neuonc/noz109

Bibtex

@article{7f98117aa2bc4bb5a68f255520de2051,
title = "Driver mutations in USP8 wild type Cushing's disease",
abstract = "BACKGROUND: Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.METHODS: Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.RESULTS: Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion.CONCLUSIONS: USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.",
author = "Silviu Sbiera and Perez-Rivas, {Luis Gustavo} and Lyudmyla Taranets and Isabel Weigand and J{\"o}rg Flitsch and Elisabeth Graf and Camelia-Maria Monoranu and Wolfgang Saeger and Christian Hagel and J{\"u}rgen Honegger and Guillaume Assie and Hermus, {Ad R} and Stalla, {G{\"u}nter K} and Sabine Herterich and Ronchi, {Cristina L} and Timo Deutschbein and Martin Reincke and Strom, {Tim M} and Nikita Popov and Marily Theodoropoulou and Martin Fassnacht",
note = "{\textcopyright} The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.",
year = "2019",
month = oct,
day = "9",
doi = "10.1093/neuonc/noz109",
language = "English",
volume = "21",
pages = "1273--1283",
journal = "NEURO-ONCOLOGY",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "10",

}

RIS

TY - JOUR

T1 - Driver mutations in USP8 wild type Cushing's disease

AU - Sbiera, Silviu

AU - Perez-Rivas, Luis Gustavo

AU - Taranets, Lyudmyla

AU - Weigand, Isabel

AU - Flitsch, Jörg

AU - Graf, Elisabeth

AU - Monoranu, Camelia-Maria

AU - Saeger, Wolfgang

AU - Hagel, Christian

AU - Honegger, Jürgen

AU - Assie, Guillaume

AU - Hermus, Ad R

AU - Stalla, Günter K

AU - Herterich, Sabine

AU - Ronchi, Cristina L

AU - Deutschbein, Timo

AU - Reincke, Martin

AU - Strom, Tim M

AU - Popov, Nikita

AU - Theodoropoulou, Marily

AU - Fassnacht, Martin

N1 - © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

PY - 2019/10/9

Y1 - 2019/10/9

N2 - BACKGROUND: Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.METHODS: Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.RESULTS: Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion.CONCLUSIONS: USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.

AB - BACKGROUND: Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.METHODS: Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.RESULTS: Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion.CONCLUSIONS: USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.

U2 - 10.1093/neuonc/noz109

DO - 10.1093/neuonc/noz109

M3 - SCORING: Journal article

C2 - 31222332

VL - 21

SP - 1273

EP - 1283

JO - NEURO-ONCOLOGY

JF - NEURO-ONCOLOGY

SN - 1522-8517

IS - 10

ER -