Sporadic pituitary adenoma with somatic double-hit loss of MEN1

Hong, Christopher S.; Alanya, Hasan; DiStasio, Marcello; Boulware, Susan D.; Rimmer, Ryan A.; Omay, Sacit Bulent; Erson-Omay, E. Zeynep

doi:10.1007/s11102-023-01336-1

Pituitary

2023

DOI: 10.1007/s11102-023-01336-1

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Sporadic pituitary adenoma with somatic double-hit loss of MEN1

Christopher S. Hong,

Hasan Alanya,

Marcello DiStasio

et al.

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2024

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Cited by 3 publications

References 45 publications

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High level of aneuploidy and recurrent loss of chromosome 11 as relevant features of somatotroph pituitary tumors

Rymuza,

Kober,

Maksymowicz

et al. 2024

J Transl Med

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Background Somatotroph neuroendocrine pituitary tumors (sPitNET) are a subtype of pituitary tumors that commonly cause acromegaly. Our study aimed to determine the spectrum of DNA copy number abnormalities (CNAs) in sPitNETs and their relevance. Methods A landscape of CNAs in sPitNETs was determined using combined whole-genome approaches involving low-pass whole genome sequencing and SNP microarrays. Fluorescent in situ hybridization (FISH) was used for microscopic validation of CNAs. The tumors were also subjected to transcriptome and DNA methylation analyses with RNAseq and microarrays, respectively. Results We observed a wide spectrum of cytogenetic changes ranging from multiple deletions, recurrent chromosome 11 loss, stable genomes, to duplication of the majority of the chromosomes. The identified CNAs were confirmed with FISH. sPitNETs with multiple duplications were characterized by intratumoral heterogeneity in chromosome number variation in individual tumor cells, as determined with FISH. These tumors were separate CNA-related sPitNET subtype in clustering analyses with CNA signature specific for whole genome doubling-related etiology. This subtype encompassed GNAS-wild type, mostly densely granulated tumors with favorable expression level of known prognosis-related genes, notably enriched with POUF1/NR5A1-double positive PitNETs. Chromosomal deletions in sPitNETs are functionally relevant. They occurred in gene-dense DNA regions and were related to genes downregulation and increased DNA methylation in the CpG island and promoter regions in the affected regions. Recurrent loss of chromosome 11 was reflected by lowered MEN1 and AIP. No such unequivocal relevance was found for chromosomal gains. Comparisons of transcriptomes of selected most cytogenetically stable sPitNETs with tumors with recurrent loss of chromosome 11 showed upregulation of processes related to gene dosage compensation mechanism in tumors with deletion. Comparison of stable tumors with those with multiple duplications showed upregulation of processes related to mitotic spindle, DNA repair, and chromatin organization. Both comparisons showed upregulation of the processes related to immune infiltration in cytogenetically stable tumors and deconvolution of DNA methylation data indicated a higher content of specified immune cells and lower tumor purity in these tumors. Conclusions sPitNETs fall into three relevant cytogenetic groups: highly aneuploid tumors characterized by known prognostically favorable features and low aneuploidy tumors including specific subtype with chromosome 11 loss.

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High level of aneuploidy and recurrent loss of chromosome 11 as relevant features of somatotroph pituitary tumors

Rymuza,

Kober,

Maksymowicz

et al. 2024

J Transl Med

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Sporadic Parathyroid Carcinoma Treated With Lenvatinib, Exhibiting a Novel Somatic MEN1 Mutation

Ito,

Imaizumi,

Daido

et al. 2024

JCEM Case Reports

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Parathyroid carcinoma (PC) is extremely rare and is primarily treated surgically. Chemotherapy is an option for advanced stages, but no standard regimen exists. Emerging research suggests the efficacy of multitarget tyrosine kinase inhibitors (MTKIs) for PC, targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). A 61-year-old Japanese woman presented with a neck mass, diagnosed as PC with pleural and lumbar metastases. After parathyroidectomy and radiation for lumbar metastasis, immunohistochemistry showed VEGFR overexpression, leading to targeted therapy with MTKIs. Despite no actionable mutations on cancer genomic panel test, a novel MEN1 somatic mutation (NM_130801: exon2: c.332delG: p.G111fs*8) was identified, which may affect VEGFR2 expression and tumor epigenetics. Although severe hand-foot syndrome necessitated dose reductions and treatment interruptions, sorafenib treatment managed hypercalcemia with evocalcet and denosumab. Lenvatinib, as second-line therapy, was effective against pleural metastases but caused thrombocytopenia and hematuria, leading to discontinuation and uncontrolled recurrence and metastasis progression. Our case highlights the need for further research on genomic profiling, molecular targets, and therapy response in PC.

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Genetic and Functional Changes in Mitochondria in the Pituitary Adenoma: The Pathogenesis and Its Therapy

Wu,

Xu,

Zhao

et al. 2024

Antioxidants

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Pituitary adenoma is a common neoplasm of the pituitary gland. Although most pituitary adenomas are benign, they can pose significant challenges in terms of their consequences and prognosis due to their tendency to invade surrounding tissues and their effects on hormone secretion. The management of pituitary adenomas typically involves surgery, medical therapy, and radiotherapy, each of which has its own limitations. Mitochondria play a crucial role in tumor development and progression by regulating various metabolic processes and signaling pathways within tumor cells and the tumor microenvironment. Multiple studies have indicated that mitochondrial dysfunction is implicated in human pituitary adenomas. Furthermore, several compounds with therapeutic effects on pituitary adenomas have been reported to target mitochondrial function. In this review, we summarize recent studies that highlight the involvement of mitochondrial homeostasis imbalance in the biology of pituitary adenomas. We conclude that mitochondria may represent a promising therapeutic target for the treatment of pituitary adenomas.

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Sporadic pituitary adenoma with somatic double-hit loss of MEN1

Cited by 3 publications

References 45 publications

High level of aneuploidy and recurrent loss of chromosome 11 as relevant features of somatotroph pituitary tumors

High level of aneuploidy and recurrent loss of chromosome 11 as relevant features of somatotroph pituitary tumors

Sporadic Parathyroid Carcinoma Treated With Lenvatinib, Exhibiting a Novel Somatic MEN1 Mutation

Genetic and Functional Changes in Mitochondria in the Pituitary Adenoma: The Pathogenesis and Its Therapy

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