Reference : Evaluation of the Molecular Pathogenesis of Adrenocortical Tumors by Whole-Genome Seq...
Scientific congresses, symposiums and conference proceedings : Paper published in a journal
Human health sciences : Endocrinology, metabolism & nutrition
Systems Biomedicine
http://hdl.handle.net/10993/47044
Evaluation of the Molecular Pathogenesis of Adrenocortical Tumors by Whole-Genome Sequencing
English
Neininger, Kerstin mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Altieri, Barbara [> >]
Lippert, Juliane L. [> >]
Roomp, Kirsten mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Dalmazi, Guido Di [> >]
Canu, Letizia [> >]
Ceccato, Filippo [> >]
Riester, Anna [> >]
Herterich, Sabine L. [> >]
Fassnacht, Martin [> >]
Schneider, Jochen mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Medical Translational Research]
Ronchi, Cristina L. [> >]
3-May-2021
Journal of the Endocrine Society
Endocrine Society
5
Issue Supplement_1
ENDO 2021 Abstracts Annual Meeting of the Endocrine Society
A68
Yes (verified by ORBilu)
No
International
2472-1972
United States
ENDO 2021
20-23 March 2021
[en] adrenocortical adenomas ; cortisol-producing adenomas with Cushing syndrome ; Whole-Genome Sequencing
[en] Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. Our aim was to identify novel genetic alterations in adrenocortical adenomas (ACA) without somatic mutations in known driver genes. Whole-genome sequencing was performed on 26 ACA/blood-derived DNA pairs without driver mutations in PRKACA, GNAS and CTNNB1 genes at previous WES (ENSAT study JCEM 2016). These included 12 cortisol-producing adenomas with Cushing syndrome (CS-CPAs), 7 with mild autonomous cortisol secretion (MACS-CPAs), and 7 endocrine-inactive ACAs (EIAs). Seven adrenocortical carcinomas (ACC) were added to the cohort. We developed a bioinformatics pipeline for a comprehensive genome analysis and to reveal differences in variant distribution. Strelka, VarScan2 and ANNOVAR software and an in-house confidence score were used for variant calling and functional annotation. Combined Annotation-Dependent-Depletion (CADD) values were used to prioritize pathogenic variants. Additional focus relied on variants in pathogenically known pathways (Wnt/β-catenin, cAMP/PKA pathway). NovoBreak algorithm was applied to discover structural variations. Two hypermutated CS-CPA samples were excluded from further analysis. Using different filters, we detected variants in driver genes not observed at WES (one p.S45P in CTNNB1 and one p.R206L in PRKACA in two different CS-CPAs). In total, we report 179,830 variations (179,598 SNVs; 232 indels) throughout all samples, being more abundant in ACC (88,954) compared to ACA (CS-CPAs: 31,821; MACS-CPAs: 35,008; EIAs: 29,963). Most alterations were in intergenic (>50%), followed by intronic and ncRNA intronic regions. A total of 32 predicted pathogenic variants were found in both coding (CADD values ≥ 15) and non-coding (CADD values ≥ 5) regions. We found 3,301 possibly damaging and recurrent variants (intergenic mutations removed) (CS-CPAs: 1,463; MACS-CPAs: 1,549; EIAs: 1,268; ACC: 1,660), mostly accumulated in intronic regions. Some of these were detected in members of the Wnt/β-catenin (CS-CPAs: 6; MACS-CPAs: 2; EIA: 1) and cAMP/PKA (CS-CPAs: 6; MACS-CPAs: 7; EIA: 4) pathways (e.g. ADCY1, ADCY2, GNA13, PDE11A). We also found a slightly higher number of structural variations in EIA (3,620) and ACC (3,486) compared to CS-CPAs (977) and MACS-CPAs (2,119). In conclusion, still unrevealed genetic alterations, especially in intronic regions, may accompany early adrenal tumorigenesis and/or autonomous cortisol secretion.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Medical Translational Research (J. Schneider Group)
Researchers ; Professionals
http://hdl.handle.net/10993/47044
10.1210/jendso/bvab048.137
https://doi.org/10.1210/jendso/bvab048.137

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