scholarly journals SAT-LB57 The Spectrum of Genomic and Transcriptomic Alterations in ACTH-Producing and ACTH-Silent Corticotroph Adenomas

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Antonio Marcondes Lerario ◽  
David Meredith ◽  
Joseph Castlen ◽  
Lauren M Johnson ◽  
Michael Catalino ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosomal Instability ◽  
Chromosomal Abnormalities ◽  
Dominant Role ◽  
Telomere Maintenance ◽  
High Morbidity ◽  
Disease Course ◽  
Loss Of Function ◽  
Aggressive Disease ◽  
Corticotroph Adenomas

Abstract Corticotroph adenomas (CA) are rare pituitary tumors that impose several challenges in clinical management - CA are difficult to diagnose, often recur, and are associated with high morbidity and mortality. CA are characteristically Tpit-positive and PIT1-negative and comprise ACTH-producing (Cushing’s disease (CD)) and ACTH-silent (AS) classes. The molecular programs contributing to disease pathogenesis in CA are still poorly characterized, largely restricted to the identification of somatic mutations in USP8 in 40-60% of CD adenomas. To more fully characterize the mutational and transcriptional landscape driving both classes of CA, we performed whole-exome sequencing and RNA-seq in 19 CD and 16 AS adenomas. We identified USP8 mutations in 53% of CD (10/19) and 6% of AS (1/16) samples. Strikingly, in 19% of AS tumors (3/16), all exhibiting an unusually aggressive disease course, including two cases with brain metastases, we identified recurrent somatic pathogenic mutations in TP53 and novel loss-of-function mutations in telomere maintenance genes DAXX and ATRX. Furthermore, while all tumors with USP8 mutations (regardless of CD/AS status) exhibited no chromosomal abnormalities as measured by copy-number variation (CNV) and loss of heterozygosity (LOH) analysis, 33% of CD (4/12, including 1 tumor with a DAXX mutation) and 36% of AS (4/11, including all DAXX/ATRX-mutated cases) samples exhibited profound chromosomal instability, characterized by hyperdiploidy, widespread whole-chromosome LOH events, and arm-level breakpoints. Using transcriptome analysis (n=22), we identified three classes of tumors (C1-C3), reflecting these distinct somatic alteration profiles. C1 tumors (n=6) are characterized by chromosomal stability, includes exclusively USP8-mutated CD, and exhibits upregulation of genes involved in metabolic processes and protein acetylation. C2 tumors (n=10) are comprised exclusively of AS (including all TP53- and/or DAXX/ATRX-mutated cases), are characterized by chromosomal instability, and exhibits concordant upregulation of cell cycle programs. Finally, C3 (n=6) contains a mixture of AS and CD cases (including CD without mutations in USP8) and features an expression profile that partly overlap with C1 tumors, but also exhibit higher expression of inflammatory genes. Taken together, our data suggest that CD and AS are distinct molecular subtypes of CA, highlighting the dominant role of USP8 mutations in driving a unique transcriptional program and illustrate for the first time that unlike most cases of CD, AS cases are characterized by profound genomic instability and cell cycle activation, features associated with a more aggressive disease course.

scholarly journals Loss of CIC promotes mitotic dysregulation and chromosome segregation defects

2019 ◽  
Author(s):  
Suganthi Chittaranjan ◽  
Jungeun Song ◽  
Susanna Y. Chan ◽  
Stephen Dongsoo Lee ◽  
Shiekh Tanveer Ahmad ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Mammalian Cells ◽  
Chromosomal Instability ◽  
Spindle Assembly Checkpoint ◽  
Tumour Suppressor ◽  
Cell Cycle Regulators ◽  
Loss Of Function ◽  
Wide Range ◽  
Cancer Types

AbstractBackgroundCIC is a transcriptional repressor inactivated by loss-of-function mutations in several cancer types, including gliomas, lung cancers, and gastric adenocarcinomas. CIC alterations and/or loss of CIC activity have been associated with poorer outcomes and more aggressive phenotypes across cancer types, which is consistent with the notion that CIC functions as a tumour suppressor across a wide range of contexts.ResultsUsing mammalian cells lacking functional CIC, we found that CIC deficiency was associated with chromosome segregation (CS) defects, resulting in chromosomal instability and aneuploidy. These CS defects were associated with transcriptional dysregulation of spindle assembly checkpoint and cell cycle regulators. We also identified novel CIC interacting proteins, including core members of the SWI/SNF complex, and showed that they cooperatively regulated the expression of genes involved in cell cycle regulation. Finally, we showed that loss of CIC and ARID1A cooperatively increased CS defects and reduced cell viability.ConclusionsOur study ascribes a novel role to CIC as an important regulator of the cell cycle and demonstrates that loss of CIC can lead to chromosomal instability and aneuploidy in human and murine cells through defects in CS, providing insight into the underlying mechanisms of CIC’s increasingly apparent role as a “pan-cancer” tumour suppressor.

Topographical analysis of telomere length and correlation with genomic instability in whole mount prostatectomies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11107-11107
Author(s):  
A. M. Joshua ◽  
P. Marrano ◽  
A. Evans ◽  
T. Van der Kwast ◽  
M. Zielenska ◽  
...  
Keyword(s):  
Telomere Length ◽  
Chromosomal Instability ◽  
Chromosomal Abnormalities ◽  
Chromosome 8 ◽  
Telomere Maintenance ◽  
Current Evidence ◽  
Telomere Shortening ◽  
Whole Mount ◽  
Trisomy 7

11107 Background: Many critical events in prostatic carcinogenesis appear to relate to the emergence of chromosomal instability and acquisition of genomic rearrangements. Characteristic abnormalities such as 8p loss, 8q gain, trisomy 7, PTEN microdeletions and TMPRSS2-ERG gene fusions appear to mediate mechanisms to increase neoplastic transformation in prostate cancer. Current evidence suggests that telomere dysfunction is a likely causative factor for some of these abnormalities on the basis of its relationship to mechanisms such as the break-fusion-bridge cycle that can lead to the onset of chromosomal instability. Methods: In this study, we correlated telomere length in various prostatic histologies by quantitative FISH with genomic markers of chromosomal instability by standard FISH and immunohistochemical measures of proliferation in 3 whole mount prostatectomies. Results: After analysing approximately 25,000 cells, we found that telomere shortening was correlated with an increase in the number of cells with abnormalities on chromosome 8, such as an increase in the average number of c-myc signals (r∼0.35, p∼0.02). However, there were no significant correlations with abnormalities such as trisomy 7 or abnormalities of the PTEN locus in any sample. Additional findings included; associations found with the probability of C-MYC aberrations in stroma with greater proximity to cancer (<1,000 um), a correlation between telomere length in a number of prostatic histologies (normal, atrophy, HPIN and cancer) with the adjacent stroma, and a lack of correlation between the Ki67 index of various histologies and their telomere length - all suggesting the importance of microenvironmental effects on telomere maintenance in the prostate. Finally, we also report significant telomere shortening in BPH in 2 cases, a phenomenon that has not been noted previously. Conclusions: This is the first study to directly link a mechanism of chromosomal instability with specific chromosomal abnormalities in prostatic carcinogenesis and also suggests that the microenvironmental milieu is of critical importance in the evolution of in vivo telomere homeostasis. No significant financial relationships to disclose.

scholarly journals Cooperation between Cyclin E and p27Kip1 in Pituitary Tumorigenesis

2010 ◽  
Vol 24 (9) ◽  
pp. 1835-1845 ◽  
Author(s):  
Audrey Roussel-Gervais ◽  
Steve Bilodeau ◽  
Sophie Vallette ◽  
France Berthelet ◽  
André Lacroix ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin E ◽  
Pituitary Tumors ◽  
Anterior Lobe ◽  
Proliferation Index ◽  
Intermediate Lobe ◽  
Loss Of Function ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Corticotroph Adenomas

Abstract Cushing’s disease is caused by glucocorticoid-resistant pituitary corticotroph adenomas. We have previously identified the loss of nuclear Brg1 as one mechanism that may lead to partial glucocorticoid resistance: this loss is observed in about 33% of human corticotroph adenomas. We now show that Brg1 loss of function correlates with cyclin E expression in corticotroph adenomas and with loss of the cell cycle inhibitor p27Kip1 expression. Because Brg1 is thought to have tumor suppressor activity, the present study was undertaken to understand the putative contribution of cyclin E derepression produced by loss of Brg1 expression on adenoma development. Overexpression of cyclin E in pituitary proopiomelanocortin cells leads to abnormal reentry into cell cycle of differentiated proopiomelanocortin cells and to centrosome instability. These alterations are consistent with the intermediate lobe hyperplasia and anterior lobe adenomas that were observed in these pituitaries. When combined with the p27Kip1 knockout, overexpression of cyclin E increased the incidence of pituitary tumors, their size, and their proliferation index. These results suggest that cyclin E up-regulation and p27Kip1 loss-of-function act cooperatively on pituitary adenoma development.

A multifaceted role for ATM in genome maintenance

2003 ◽  
Vol 5 (16) ◽  
pp. 1-21 ◽  
Author(s):  
Tej K. Pandita
Keyword(s):  
Cell Cycle ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Telomere Maintenance ◽  
Loss Of Function ◽  
Genome Maintenance ◽  
Ataxia Telangiectasia Mutated ◽  
Gonadal Atrophy ◽  
Mitogenic Signal Transduction

The pleiotropic nature of the clinical phenotypes of patients with ataxia-telangiectasia (A-T) – which encompass cerebellar degeneration (leading to ataxia), gonadal atrophy, and cancer predisposition – suggests multiple functions of the gene responsible for the disease. The ataxia-telangiectasia mutated gene product (ATM), whose loss of function is responsible for ataxia-telangiectasia, is a protein kinase that interacts with several substrates and is implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control and telomere maintenance. This review focuses on the critical roles that ATM appears to play in cell-cycle checkpoints, DNA repair, telomere metabolism and oxidative stress, indicating how defects in these processes might lead to ataxia-telangiectasia.

scholarly journals Deregulation of Rb-E2F1 Axis Causes Chromosomal Instability by Engaging the Transactivation Function of Cdc20–Anaphase-Promoting Complex/Cyclosome

2014 ◽  
Vol 35 (2) ◽  
pp. 356-369 ◽  
Author(s):  
Somsubhra Nath ◽  
Abhishek Chowdhury ◽  
Sanjib Dey ◽  
Anirban Roychoudhury ◽  
Abira Ganguly ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosomal Instability ◽  
Spindle Assembly Checkpoint ◽  
Chromosomal Abnormalities ◽  
Transcriptional Regulator ◽  
Carrier Protein ◽  
Dna Binding Domain ◽  
Anaphase Promoting Complex ◽  
Mitotic Progression ◽  
Mitotic Regulation

The E2F family of transcription factors regulates genes involved in various aspects of the cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by the spindle assembly checkpoint (SAC). The SAC ensures bipolar separation of chromosomes and thus prevents aneuploidy. There are limited reports on the regulation of the SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of the mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here we show that an E2F1-DP1 heterodimer is involved in recruitment of the Cdc20 transcription complex to theUBCH10promoter and in transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities, and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits the complex of Cdc20 and the anaphase-promoting complex/cyclosome (Cdc20-APC/C) to deregulate the expression ofUBCH10, leading to chromosomal instability in cancer cells.

scholarly journals Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanne Fransson ◽  
Angela Martinez-Monleon ◽  
Mathias Johansson ◽  
Rose-Marie Sjöberg ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Mapk Signaling ◽  
Telomere Maintenance ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Cycle Progression

AbstractNeuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

scholarly journals β-elemene alleviates airway stenosis via the ILK/Akt pathway modulated by MIR143HG sponging miR-1275

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Guoying Zhang ◽  
Cheng Xue ◽  
Yiming Zeng
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Cell Model ◽  
Protective Efficacy ◽  
Rabbit Model ◽  
Akt Pathway ◽  
Loss Of Function ◽  
Airway Stenosis

Abstract Background We have previously found that β-elemene could inhibit the viability of airway granulation fibroblasts and prevent airway hyperplastic stenosis. This study aimed to elucidate the underlying mechanism and protective efficacy of β-elemene in vitro and in vivo. Methods Microarray and bioinformatic analysis were used to identify altered pathways related to cell viability in a β-elemene-treated primary cell model and to construct a β-elemene-altered ceRNA network modulating the target pathway. Loss of function and gain of function approaches were performed to examine the role of the ceRNA axis in β-elemene's regulation of the target pathway and cell viability. Additionally, in a β-elemene-treated rabbit model of airway stenosis, endoscopic and histological examinations were used to evaluate its therapeutic efficacy and further verify its mechanism of action. Results The hyperactive ILK/Akt pathway and dysregulated LncRNA-MIR143HG, which acted as a miR-1275 ceRNA to modulate ILK expression, were suppressed in β-elemene-treated airway granulation fibroblasts; β-elemene suppressed the ILK/Akt pathway via the MIR143HG/miR-1275/ILK axis. Additionally, the cell cycle and apoptotic phenotypes of granulation fibroblasts were altered, consistent with ILK/Akt pathway activity. In vivo application of β-elemene attenuated airway granulation hyperplasia and alleviated scar stricture, and histological detections suggested that β-elemene's effects on the MIR143HG/miR-1275/ILK axis and ILK/Akt pathway were in line with in vitro findings. Conclusions MIR143HG and ILK may act as ceRNA to sponge miR-1275. The MIR143HG/miR-1275/ILK axis mediates β-elemene-induced cell cycle arrest and apoptosis of airway granulation fibroblasts by modulating the ILK/Akt pathway, thereby inhibiting airway granulation proliferation and ultimately alleviating airway stenosis.

scholarly journals The Constitutive Centromere Component CENP-50 Is Required for Recovery from Spindle Damage

2005 ◽  
Vol 25 (23) ◽  
pp. 10315-10328 ◽  
Author(s):  
Yukinori Minoshima ◽  
Tetsuya Hori ◽  
Masahiro Okada ◽  
Hiroshi Kimura ◽  
Tokuko Haraguchi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Mitotic Checkpoint ◽  
Loss Of Function ◽  
Wild Type ◽  
Centromere Function ◽  
Dt40 Cells ◽  
Precise Role ◽  
Chicken Dt40 Cell

ABSTRACT We identified CENP-50 as a novel kinetochore component. We found that CENP-50 is a constitutive component of the centromere that colocalizes with CENP-A and CENP-H throughout the cell cycle in vertebrate cells. To determine the precise role of CENP-50, we examined its role in centromere function by generating a loss-of-function mutant in the chicken DT40 cell line. The CENP-50 knockout was not lethal; however, the growth rate of cells with this mutation was slower than that of wild-type cells. We observed that the time for CENP-50-deficient cells to complete mitosis was longer than that for wild-type cells. Centromeric localization of CENP-50 was abolished in both CENP-H- and CENP-I-deficient cells. Coimmunoprecipitation experiments revealed that CENP-50 interacted with the CENP-H/CENP-I complex in chicken DT40 cells. We also observed severe mitotic defects in CENP-50-deficient cells with apparent premature sister chromatid separation when the mitotic checkpoint was activated, indicating that CENP-50 is required for recovery from spindle damage.

scholarly journals Clinical analysis of 40 multiple myeloma patients with extramedullary plasmacytoma of the head

2016 ◽  
Vol 44 (6) ◽  
pp. 1462-1473 ◽  
Author(s):  
Wan-jun Sun ◽  
Jia-jia Zhang ◽  
Na An ◽  
Men Shen ◽  
Zhong-xia Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Characteristics ◽  
Median Overall Survival ◽  
Progression Free Survival ◽  
Clinical Analysis ◽  
Extramedullary Plasmacytoma ◽  
Disease Course ◽  
Combined Chemotherapy ◽  
Free Survival ◽  
Aggressive Disease

Objectives To investigate the clinical characteristics, survival and prognosis of patients with multiple myeloma (MM) and head extramedullary plasmacytoma (EMP). Methods Forty MM patients were enrolled in the study (18 men, 22 women; median age, 55 years). Results Median overall survival (OS) and progression-free survival (PFS) were 24 (5–78) months and 17 (2–36) months, respectively. The 2-, 3- and 5-year OS rates were 51%, 20% and 7%, respectively. The 2-year PFS was 15%. Median OS and PFS in patients administered velcade were 26 (18–50) and 22.5 (5–78) months, compared with 20 (10–30) and 13.5 (2–36) months in patients without velcade, respectively. Median OS was 23.5 (5–50) months in patients with EMP at MM diagnosis ( n = 25) and 36 (22–78) months in patients with head EMP diagnosed during the disease course ( n = 15). Sixteen MM patients had EMP invasion of the head only and 24 had invasion at multiple sites. Median OS was 25 (22–78) months in patients with EMP of the head only and 22 (5–78) months in patients with EMP invasion at multiple sites. Conclusion MM patients with head EMP show a more aggressive disease course and shorter OS and PFS. The prognosis of these patients is poor, especially in patients with head EMP at MM diagnosis, though combined chemotherapy and radiotherapy may prolong survival.

scholarly journals p53 upregulated by HIF-1α promotes hypoxia-induced G2/M arrest and renal fibrosis in vitro and in vivo

2018 ◽  
Vol 11 (5) ◽  
pp. 371-382 ◽  
Author(s):  
Limin Liu ◽  
Peng Zhang ◽  
Ming Bai ◽  
Lijie He ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activation ◽  
Renal Fibrosis ◽  
Intraperitoneal Administration ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
P53 Expression ◽  
Tubular Cells

Abstract Hypoxia plays an important role in the genesis and progression of renal fibrosis. The underlying mechanisms, however, have not been sufficiently elucidated. We examined the role of p53 in hypoxia-induced renal fibrosis in cell culture (human and rat renal tubular epithelial cells) and a mouse unilateral ureteral obstruction (UUO) model. Cell cycle of tubular cells was determined by flow cytometry, and the expression of profibrogenic factors was determined by RT-PCR, immunohistochemistry, and western blotting. Chromatin immunoprecipitation and luciferase reporter experiments were performed to explore the effect of HIF-1α on p53 expression. We showed that, in hypoxic tubular cells, p53 upregulation suppressed the expression of CDK1 and cyclins B1 and D1, leading to cell cycle (G2/M) arrest (or delay) and higher expression of TGF-β, CTGF, collagens, and fibronectin. p53 suppression by siRNA or by a specific p53 inhibitor (PIF-α) triggered opposite effects preventing the G2/M arrest and profibrotic changes. In vivo experiments in the UUO model revealed similar antifibrotic results following intraperitoneal administration of PIF-α (2.2 mg/kg). Using gain-of-function, loss-of-function, and luciferase assays, we further identified an HRE3 region on the p53 promoter as the HIF-1α-binding site. The HIF-1α–HRE3 binding resulted in a sharp transcriptional activation of p53. Collectively, we show the presence of a hypoxia-activated, p53-responsive profibrogenic pathway in the kidney. During hypoxia, p53 upregulation induced by HIF-1α suppresses cell cycle progression, leading to the accumulation of G2/M cells, and activates profibrotic TGF-β and CTGF-mediated signaling pathways, causing extracellular matrix production and renal fibrosis.

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