scholarly journals Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles

Pituitary ◽  
2021 ◽  
Author(s):  
Christian Hagel ◽  
Ulrich Schüller ◽  
Jörg Flitsch ◽  
Ulrich J. Knappe ◽  
Udo Kellner ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Copy Number ◽  
Pituitary Hormone ◽  
Null Cell ◽  
Global Methylation ◽  
Available N ◽  
Multiple Lesions ◽  
Molecular Features ◽  
Lineage Markers ◽  
Double Adenomas

Abstract Purpose Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (null cell PA) or the pituitary hormone(s) of the cell lineage of origin. In 0.5–1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown. Methods Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA). Results In accordance with the literature, combinations of GH/prolactin/TSH–FSH/LH adenoma (4/12), GH/prolactin/TSH–ACTH adenoma (3/12), and ACTH–FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern. Conclusion Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct cell types.

scholarly journals Characterization of Gonadotroph Pituitary Adenomas Based on the Recent 2017 WHO Pituitary Tumor Classification

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A640-A641
Author(s):  
Aviva Cohn ◽  
Chloe Yang Ling Li ◽  
Samantha Elena Hoffman ◽  
Ana Paula Abreu-Metzger ◽  
Joseph Castlen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cavernous Sinus ◽  
Tumor Size ◽  
Pituitary Adenomas ◽  
World Health ◽  
Pituitary Hormone ◽  
Pituitary Insufficiency ◽  
Null Cell ◽  
Cavernous Sinus Invasion

Abstract Introduction: More than 20% of pituitary adenomas are nonfunctional, the majority of which are of gonadotroph origin. Whereas previously, immunohistochemistry of pituitary hormones was used to classify adenoma subtypes, in 2017 the World Health Organization (WHO) reclassified pituitary adenomas using transcription factor expression in addition to immunohistochemistry. With this change, clinically nonfunctional gonadotroph adenomas can be distinguished among: (1) those staining for the transcription factor SF-1 and gonadotropins FSH and/or LH (FSH/LH+), (2) those that stain for SF-1 but not for FSH or LH (FSH/LH- SF1+), and (3) true null cell adenomas. It is unclear whether these three subgroups behave similarly clinically, or if they have distinct manifestations or outcomes. Our aim was to characterize these subgroups in regard to tumor size, recurrence and pituitary insufficiency. Methods: In a retrospective chart review, 71 patients from 2017-2020 who presented to the hospital for transsphenoidal resection of clinically nonfunctioning pituitary adenomas were reviewed. All patients with pituitary adenomas that stained positive for SF-1 and negative for T-PIT and PIT-1, and tumors that were negative for all three transcription factors were evaluated. Those lacking clinical data were excluded. Clinical characteristics examined include: demographics, tumor size, invasion of cavernous sinus, and hormone deficiencies. Results: Of the 71 pituitary tumors, 45% (n=32) stained positive for the beta subunit FSH and/or LH (FSH/LH+) and SF-1, 44% (n=31) stained for SF-1 with negative pituitary hormone stains (FSH/LH- SF1+), and 11% (n=8) were negative for all transcription factors and hormones (true null). All tumors were macroadenomas (>1 cm). While there were >50% males in the FSH/LH+ and FSH/LH- SF1+ groups, in the true null group only 25% of patients were male. Most patients were >50 years old in all 3 groups (81% FSH/LH+, 75% FSH/LH- SF1+, 88% true null). The prevalence of cavernous sinus involvement was 36% in both groups that stained for SF-1, but was 62% in the true null group. Both SF-1+ groups had similar tumor sizes and prevalence of panhypopituitarism (15-21%), but there were more episodes of recurrence since last known follow up in the FSH/LH- SF1+ group (20%), compared to FSH/LH+ tumors (7%). The true null group had ≥50% rates for both panhypopituitarism and recurrence. Conclusions: In this study, we highlighted the category of FSH/LH- SF1+ gonadotroph adenomas and compared these to FSH/LH+ and true null cell tumors. Based on clinical features, FSH/LH- SF1+ gonadotroph adenomas are similar to FSH/LH+ staining pituitary adenomas in regard to age, sex, size, and degree of cavernous sinus invasion, although there were more recurrences in the FSH/LH- SF1+ group. Though less common, our cohort suggests more aggressive tendencies in the true null group compared to SF-1 staining tumors.

scholarly journals Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raimonda Kubiliute ◽  
Indre Januskeviciene ◽  
Ruta Urbanaviciute ◽  
Kristina Daniunaite ◽  
Monika Drobniene ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Protein Level ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Common Mechanism ◽  
Dna Hypomethylation ◽  
Mesenchymal Transition ◽  
Molecular Features

AbstractHyperactivation of ABC transporter ABCB1 and induction of epithelial–mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisition of doxorubicin (DOX) resistance in breast cancer MX-1 cell line. DOX resistance in MX-1 cell line was induced by a stepwise increase of drug concentration or by pretreatment of cells with an ABCB1 transporter activator tetraphenylphosphonium (TPP+) followed by DOX exposure. Transcriptome analysis of derived cells was performed by human gene expression microarrays and by quantitative PCR. Genetic and epigenetic mechanisms of ABCB1 regulation were evaluated by pyrosequencing and gene copy number variation analysis. Gradual activation of canonical EMT transcription factors with later activation of ABCB1 at the transcript level was observed in DOX-only treated cells, while TPP+ exposure induced considerable activation of ABCB1 at both, mRNA and protein level. The changes in ABCB1 mRNA and protein level were related to the promoter DNA hypomethylation and the increase in gene copy number. ABCB1-active cells were highly resistant to DOX and showed morphological and molecular features of EMT. The study suggests that nongenotoxic ABCB1 inducer can possibly accelerate development of DOX resistance.

scholarly journals Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1234
Author(s):  
Jérôme Raffenne ◽  
Fernando A. Martin ◽  
Rémy Nicolle ◽  
Marina Konta ◽  
Yuna Blum ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Protein Identification ◽  
Molecular Profile ◽  
Global Methylation ◽  
Old Patients ◽  
Molecular Features ◽  
Age Related ◽  
Clinical Difference ◽  
Dna Repair Gene

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (≤55 y.o.) and 316 LOT (≥70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT.

scholarly journals High copy number variations, particular transcription factors, and low immunity contribute to the stemness of prostate cancer cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zao Dai ◽  
Ping Liu
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Copy Number Variation ◽  
Cancer Cells ◽  
Immune Cells ◽  
Copy Number ◽  
Tumor Metastasis ◽  
Prostate Cancer Cells ◽  
Immune Microenvironment ◽  
Number Variation

Abstract Background Tumor metastasis is the main cause of death of cancer patients, and cancer stem cells (CSCs) is the basis of tumor metastasis. However, systematic analysis of the stemness of prostate cancer cells is still not abundant. In this study, we explore the effective factors related to the stemness of prostate cancer cells by comprehensively mining the multi-omics data from TCGA database. Methods Based on the prostate cancer transcriptome data in TCGA, gene expression modules that strongly relate to the stemness of prostate cancer cells are obtained with WGCNA and stemness scores. Copy number variation of stemness genes of prostate cancer is calculated and the difference of transcription factors between prostate cancer and normal tissues is evaluated by using CNV (copy number variation) data and ATAC-seq data. The protein interaction network of stemness genes in prostate cancer is constructed using the STRING database. Meanwhile, the correlation between stemness genes of prostate cancer and immune cells is analyzed. Results Prostate cancer with higher Gleason grade possesses higher cell stemness. The gene set highly related to prostate cancer stemness has higher CNV in prostate cancer samples than that in normal samples. Although the transcription factors of stemness genes have similar expressions, they have different contributions between normal and prostate cancer tissues; and particular transcription factors enhance the stemness of prostate cancer, such as PUM1, CLOCK, SP1, TCF12, and so on. In addition, the lower tumor immune microenvironment is conducive to the stemness of prostate cancer. CD8 + T cells and M1 macrophages may play more important role in the stemness of prostate cancer than other immune cells in the tumor microenvironment. Finally, EZH2 is found to play a central role in stemness genes and is negatively correlated with resting mast cells and positively correlated with activated memory CD4 + T cells. Conclusions Based on the systematic and combined analysis of multi-omics data, we find that high copy number variation, specific transcription factors, and low immune microenvironment jointly contribute to the stemness of prostate cancer cells. These findings may provide us new clues and directions for the future research on stemness of prostate cancer.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

2016 ◽  
Vol 174 (6) ◽  
pp. R239-R247 ◽  
Author(s):  
Frederic Castinetti ◽  
Rachel Reynaud ◽  
Alexandru Saveanu ◽  
Nicolas Jullien ◽  
Marie Helene Quentien ◽  
...  
Keyword(s):  
Transcription Factors ◽  
G Protein Coupled Receptors ◽  
Hormone Deficiency ◽  
Immunoglobulin Superfamily ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Signalling Molecules ◽  
Genes Encoding ◽  
G Protein Coupled

Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations ofPOU1F1orPROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

Association of genes copy number in extracellular DNA in patients with prostate cancer and sensitivity to radiotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15014-e15014
Author(s):  
Denis S. Kutilin ◽  
Mikhail S. Zinkovich ◽  
Marina A. Gusareva ◽  
Aleksandr V. Faenson ◽  
Elena A. Karnauhova ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Blood Plasma ◽  
Copy Number ◽  
Extracellular Dna ◽  
Biochemical Relapse ◽  
Prostate Tumors ◽  
Molecular Features ◽  
Number Variation ◽  
Invasive Method ◽  
High Level

e15014 Background: Radiotherapy (RT) is one of the main treatments for prostate cancer (PC). The effectiveness of such therapy depends on the initial radioresistance of tumor cells, which is ensured by their certain molecular features, which include the genes copy number variation (CNV). Model experiments on cell cultures (obtained from surgical material) have shown that CNVs have high potential as predictors of RT sensitivity. However, this potential is limited by the high level of invasiveness in obtaining biomaterials. A possible solution to this problem lies in the transition to CNV study in the extracellular DNA (cfDNA) of blood plasma. The aim of the study was to screen predictors of radioresistant PC based on the genes CNV in cfDNA. Methods: The study included 400 patients with diagnosed PC (T2a-3bN0M0, st. II-III), 40 of them after RT had a state of biochemical relapse (RT was performed on a Novalis TX linear accelerator (Varian, USA) (TFDisoeff = 75 Gr), mean time to biochemical relapse 7.5 months). Blood samples were separated into plasma and cell fraction by centrifugation. Isolation of cfDNA from blood plasma was performed using a set of reagents “DNA-Plasma-M” (Russia). Determination of the relative CNV of 13 genes (CDK1, CCND3, CDKN1B, TP53, PTEN, BCL2, XRCC4, BAX, RBBP8, H2AX, BRCA2, RAD50, EP300) was performed using the Real-Time qPCR method. Differences were assessed using the Mann-Whitney test; the Benjamin-Hochberg correction was used to correct multiple comparisons. Results: In the group with biochemical relapse (n = 40), the CNV of genes CDK1, CDKN1B, RBBP8, XRCC4, BRCA2 and RAD50 was statistically significantly (p < 0.05) higher by 2.0 times, 2.3 times, 2.1 times, 1.4 times, 2.4 times and 2.8 times, respectively, relative to the CNV of these genes in the cfDNA of the group without relapse (n = 360). Conclusions: Thus, it was found that the CNV of 6 genes (CDK1, CDKN1B, RBBP8, XRCC4, BRCA2 and RAD50) may be a potential molecular marker of radiosensitivity of prostate tumors. Based on the obtained data, a low invasive method for determining the prostate tumors sensitivity to RT has been developed.

Immunonegative "Null Cell" Adenomas and Gonadotropin (Gn) Subunit (SUs) Immunopositive Adenomas Share Frequent Expression of Multiple Transcription Factors

2006 ◽  
Vol 17 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Yudo Ishii ◽  
Masanori Suzuki ◽  
Susumu Takekoshi ◽  
Noboru Egashira ◽  
Michio Yamazaki ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Null Cell ◽  
Null Cell Adenomas

scholarly journals Mouse conventional dendritic cells can be universally classified based on the mutually exclusive expression of XCR1 and SIRPα

2014 ◽  
Author(s):  
Stephanie Gurka ◽  
Evelyn Hartung ◽  
Martina Becker ◽  
Richard A. Kroczek
Keyword(s):  
Dendritic Cells ◽  
Transcription Factors ◽  
Present Article ◽  
Classification Systems ◽  
Surface Molecule ◽  
New Classification ◽  
Surface Molecules ◽  
Lineage Markers ◽  
Future Work ◽  
Activation Status

Since the identification of mouse dendritic cells (DC) in the early 70s, all attempts to consistently classify the identified functional DC subpopulations according to their surface molecule expression failed. In the absence of DC lineage markers, a great variety of non-congruent surface molecules were used instead. Recently advances in the understanding of the involvement of transcription factors in the differentiation of DC subpopulations, together with the identification of a lineage marker for cross-presenting DC, has now allowed to establish a consistent and unified DC classification in the mouse. We demonstrate in the present article that all conventional DC in the mouse can be universally subdivided into either XCR1+ cross-presenting DC or SIRPα+ DC, irrespective of their activation status. This advancement will greatly facilitate future work on the biology of mouse DC. We discuss this new classification in view of current DC classification systems in the mouse and the human.

scholarly journals Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 574
Author(s):  
Ege Ülgen ◽  
Sıla Karacan ◽  
Umut Gerlevik ◽  
Özge Can ◽  
Kaya Bilguvar ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Alteration ◽  
Age At Diagnosis ◽  
Copy Number Alterations ◽  
Primary Tumors ◽  
Double Minutes ◽  
Molecular Features ◽  
Genetic Landscape ◽  
Underlying Mechanisms ◽  
Mutational Processes

Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and “Others” differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.

scholarly journals Determinants of correlated expression of transcription factors and their target genes

2020 ◽  
Vol 48 (20) ◽  
pp. 11347-11369
Author(s):  
Adam B Zaborowski ◽  
Dirk Walther
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
High Expression ◽  
Binding Motifs ◽  
Protein Protein Interaction ◽  
Correlation Distribution ◽  
Molecular Features ◽  
Molecular Determinants ◽  
Physical Interactions ◽  
Plant Arabidopsis Thaliana

Abstract While transcription factors (TFs) are known to regulate the expression of their target genes (TGs), only a weak correlation of expression between TFs and their TGs has generally been observed. As lack of correlation could be caused by additional layers of regulation, the overall correlation distribution may hide the presence of a subset of regulatory TF–TG pairs with tight expression coupling. Using reported regulatory pairs in the plant Arabidopsis thaliana along with comprehensive gene expression information and testing a wide array of molecular features, we aimed to discern the molecular determinants of high expression correlation of TFs and their TGs. TF-family assignment, stress-response process involvement, short genomic distances of the TF-binding sites to the transcription start site of their TGs, few required protein-protein-interaction connections to establish physical interactions between the TF and polymerase-II, unambiguous TF-binding motifs, increased numbers of miRNA target-sites in TF-mRNAs, and a young evolutionary age of TGs were found particularly indicative of high TF–TG correlation. The modulating roles of post-transcriptional, post-translational processes, and epigenetic factors have been characterized as well. Our study reveals that regulatory pairs with high expression coupling are associated with specific molecular determinants.

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