Genetic Basis of ACTH-Secreting Adenomas

Locantore, Pietro; Paragliola, Rosa Maria; Cera, Gianluca; Novizio, Roberto; Maggio, Ettore; Ramunno, Vittoria; Corsello, Andrea; Corsello, Salvatore Maria

doi:10.3390/ijms23126824

Cited by 3 publications

(1 citation statement)

References 113 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This activity contributes to the fine-tuning of signaling cascades involved in cell growth, proliferation, and differentiation (42)(43)(44)(45). Somatic mutations of the USP8 gene have been found in adenomas causing Cushing's disease (46)(47)(48), and abnormal expression of USP8 has been found in various neoplasms (43,49,50). The Mitelman database of chromosome aberrations and gene fusions in cancer has documented 14 chimeric genes involving USP8, including a fusion between USP8 and lysine methyltransferase 2A (KMT2A) in B-cell lineage acute lymphoplastic leukemia.…”

Section: Discussionmentioning

confidence: 99%

Fusion of Platelet Derived Growth Factor Receptor Alpha (PDGFRA) With Ubiquitin Specific Peptidase 8 (USP8) in a Calcified Chondroid Mesenchymal Neoplasm Harboring t(4;15)(q12;q21) as a Sole Aberration

PANAGOPOULOS,

ANDERSEN,

GORUNOVA

et al. 2024

Cancer Genomics Proteomics

View full text Add to dashboard Cite

Background/Aim: The term "calcified chondroid mesenchymal neoplasm" was introduced in 2021 to describe a group of tumors characterized by various morphological features, including the formation of cartilage or chondroid matrix. These tumors frequently carry chimeric genes where the 5´-end partner gene is fibronectin 1 and the 3´-end partner gene codes for receptor tyrosine kinase. Our study explores fusion of the genes platelet-derived growth factor receptor alpha (PDGFRA) and ubiquitin-specific peptidase 8 (USP8) in calcified chondroid mesenchymal neoplasm. Case Report: Genetic investigations were conducted on a tumor located in the leg of a 71-year-old woman. G-banding analysis of short-term cultured tumor cells revealed the karyotype 46,XX,t(4;15)(q12;q21)[6]/46,XX [4]. RNA sequencing detected in-frame PDGFRA::USP8 and USP8::PDGFRA chimeric transcripts, which were validated by RT-PCR/Sanger sequencing. The PDGFRA::USP8 chimeric protein is predicted to have cell membrane location and functions as a chimeric ubiquitinyl hydrolase. The USP8::PDGFRA protein was predicted to be nuclear and function as a positive regulator of cellular metabolic process. Conclusion: We report, for the first time, a calcified chondroid mesenchymal neoplasm carrying a balanced t(4;15)(q12;q21) chromosomal translocation, resulting in the generation of both PDGFRA::USP8 and USP8::PDGFRA chimeras. The PDGFRA::USP8 protein is located on the cell membrane and functions as a chimeric ubiquitinyl hydrolase, activated by PDGFs. Conversely, USP8::PDGFRA is a nuclear protein regulating metabolic processes.

show abstract

Section: Discussionmentioning

confidence: 99%

Fusion of Platelet Derived Growth Factor Receptor Alpha (PDGFRA) With Ubiquitin Specific Peptidase 8 (USP8) in a Calcified Chondroid Mesenchymal Neoplasm Harboring t(4;15)(q12;q21) as a Sole Aberration

PANAGOPOULOS,

ANDERSEN,

GORUNOVA

et al. 2024

Cancer Genomics Proteomics

View full text Add to dashboard Cite

show abstract

Expression Characteristics of Immune Cells and Related Molecules in Hypertension Patients

Wei

Tang

Tian

et al. 2023

Preprint

View full text Add to dashboard Cite

USP8 Mutations Associated with Cushing’s Disease Alter Protein Structure Dynamics

Petukhova,

Poluzerova,

Bug

et al. 2024

IJMS

View full text Add to dashboard Cite

The adenomas in Cushing’s disease frequently exhibit mutations in exon 14, within a binding motif for the regulatory protein 14-3-3 located between the catalytic domain (DUB), responsible for ubiquitin hydrolysis, and the WW-like domain that mediates autoinhibition, resulting in constantly active USP8. The exact molecular mechanism of deubiquitinase activity disruption in Cushing’s disease remains unclear. To address this, Sanger sequencing of USP8 was performed to identify mutations in corticotropinomas. These mutations were subjected to computational screening, followed by molecular dynamics simulations to assess the structural alterations that might change the biological activity of USP8. Eight different variants of the USP8 gene were identified both within and outside the “hotspot” region. Six of these had previously been reported in Cushing’s disease, while two were detected for the first time in our patients with CD. One of the two new variants, initially classified as benign during screening, was found in the neighboring SH3 binding motif at a distance of 20 amino acids. This variant demonstrated pathogenicity patterns similar to those of known pathogenic variants. All USP8 variants identified in our patients caused conformational changes in the USP8 protein in a similar manner. The identified mutations, despite differences in annotation results—including evolutionary conservation assessments, automated predictor data, and variations in localization within exon 14—exhibit similar patterns of protein conformational change. This suggests a pathogenic effect that contributes to the development of CD.

show abstract

Genetic Basis of ACTH-Secreting Adenomas

Cited by 3 publications

References 113 publications

Fusion of Platelet Derived Growth Factor Receptor Alpha (PDGFRA) With Ubiquitin Specific Peptidase 8 (USP8) in a Calcified Chondroid Mesenchymal Neoplasm Harboring t(4;15)(q12;q21) as a Sole Aberration

Fusion of Platelet Derived Growth Factor Receptor Alpha (PDGFRA) With Ubiquitin Specific Peptidase 8 (USP8) in a Calcified Chondroid Mesenchymal Neoplasm Harboring t(4;15)(q12;q21) as a Sole Aberration

Expression Characteristics of Immune Cells and Related Molecules in Hypertension Patients

USP8 Mutations Associated with Cushing’s Disease Alter Protein Structure Dynamics

Contact Info

Product

Resources

About