TY  - JOUR
A1  - Sbiera, Silviu
A1  - Kunz, Meik
A1  - Weigand, Isabel
A1  - Deutschbein, Timo
A1  - Dandekar, Thomas
A1  - Fassnacht, Martin
T1  - The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight
JF  - Cancers
N2  - Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways.
KW  - Cushing’s disease
KW  - pathogenesis
KW  - somatic mutations
KW  - deubiquitinases
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193194
SN  - 2072-6694
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Williams, Richard D.
A1  - Chagtai, Tasnim
A1  - Alcaide-German, Marisa
A1  - Apps, John
A1  - Wegert, Jenny
A1  - Popov, Sergey
A1  - Vujanic, Gordan
A1  - Van Tinteren, Harm
A1  - Van den Heuvel-Eibrink, Marry M
A1  - Kool, Marcel
A1  - De Kraker, Jan
A1  - Gisselsson, David
A1  - Graf, Norbert
A1  - Gessler, Manfred
A1  - Pritchard-Jones, Kathy
T1  - Multiple mechanisms of MYCN dysregulation in Wilms tumour
JF  - Oncotarget
N2  - Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.
KW  - integrative genomics viewer
KW  - oncogene amplification
KW  - sequencing data
KW  - gene
KW  - gain
KW  - copy number
KW  - somatic mutations
KW  - beta-catenin
KW  - histology
KW  - reveals
KW  - Wilms tumour
KW  - MYCN
KW  - DNA methylation
KW  - prognostic marker
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143471
VL  - 6
IS  - 9
ER  -