Characterizing the molecular and immunological features of lung micropapillary adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21036-e21036
Author(s):  
Shirong Zhang ◽  
Yang Xu ◽  
Pan Zhao ◽  
Hua Bao ◽  
Xiyong Wang ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Kinase Inhibitor ◽  
Validation Cohort ◽  
Chromosome Instability ◽  
Mammalian Target Of Rapamycin ◽  
Angiogenesis Inhibitor ◽  
Genetic Alterations ◽  
Potential Candidate ◽  
Discovery Cohort ◽  
Histologic Subtypes

e21036 Background: Micropapillary adenocarcinoma (MPC) is one of the most aggressive histologic subtypes of lung adenocarcinoma (ADC). Although the incidence of MPC predominant ADC is low, nearly half of ADCs contain a minor proportion of MPC, which could contribute to poor prognosis in these patients. Comprehensive analysis of genetic and immunological features of ADC with different MPC contents would help better understand cancer biology of this ADC subtype and direct future treatments. Methods: We performed panel next-generation sequencing (NGS) of 425 cancer-related genes for a discovery cohort of 43 ADC patients whose tumors were microdissected to separate MPC and non-MPC regions and a reference cohort of 113 ADC patients with unknown ADC histologic subtypes. MPC-enriched mutations were identified by comparing tumors with different original MPC contents within these cohorts, which was then confirmed using a validation cohort of 183 ADC patients. Staining of immunological markers was also conducted for MPC samples from the discovery cohort to investigate their tumor microenvironment. Results: We found that ADC tumors with higher MPC contents/similarities tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). In addition, genetic alterations in transcription termination factor 1 ( TTF1), brain-specific angiogenesis inhibitor 3 ( BAI3), mammalian target of rapamycin ( MTOR), cyclin-dependent kinase inhibitor 2A ( CDKN2A), and CDKN2A were found to be enriched in MPC using the discovery and reference cohorts, which could then be cross-validated using the validation cohort. Tumors with higher MPC content were associated with elevated infiltration of CD4+, CD8+ and FOXP3+ T cells, especially at the peritumor regions. Higher percentage of PD-L1+ tumor cells were also found to be correlated with higher MPC content, suggesting of more immunosuppression in MPC predominant tumors than low MPC tumors. Conclusions: We identified multiple novel MPC-enriched genetic changes that could help understand the nature of MPC. MPC predominant tumors tended to have higher levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, making it a potential candidate for immunotherapy, especially the combination therapy of anti-PD-1/PD-L1 drugs and anti-CTLA-4 drugs, which could inhibit PD-1/PD-L1 pathway and FOXP3+ Treg cells simultaneously.

scholarly journals Integrated Analysis of Genomic and Immunological Features in Lung Adenocarcinoma With Micropapillary Component

2021 ◽  
Vol 11 ◽  
Author(s):  
Shirong Zhang ◽  
Yang Xu ◽  
Pan Zhao ◽  
Hua Bao ◽  
Xiyong Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Biology ◽  
Kinase Inhibitor ◽  
Chromosome Instability ◽  
Angiogenesis Inhibitor ◽  
Genetic Alterations ◽  
Integrated Analysis ◽  
Discovery Cohort ◽  
Genetic Changes ◽  
Micropapillary Component

BackgroundMicropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.MethodsWe performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort.ResultsTumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including MET amplification and MTOR mutation, were correlated with increased PD-L1 expression.ConclusionWe identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.

scholarly journals Cellular Signaling Pathway Alterations and Potential Targeted Therapies for Medullary Thyroid Carcinoma

2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Serena Giunti ◽  
Alessandro Antonelli ◽  
Andrea Amorosi ◽  
Libero Santarpia
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cellular Signaling ◽  
Locally Advanced ◽  
Mammalian Target Of Rapamycin ◽  
Genetic Alterations ◽  
Great Promise ◽  
Medullary Thyroid

Parafollicular C-cell-derived medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular therapies that inhibit rearranged during transfection (RET) and other tyrosine kinase receptors that are mainly involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC. Multi-tyrosine kinase inhibitors such as vandetanib, which is already approved for the treatment of progressive MTC, and cabozantinib have shown distinct advantages with regard to rates of disease response and control. However, these types of tyrosine kinase inhibitor compounds are able to concurrently block several types of targets, which limits the understanding of RET as a specific target. Moreover, important resistances to tyrosine kinase inhibitors can occur, which limit the long-term efficacy of these treatments. Deregulated cellular signaling pathways and genetic alterations in MTC, particularly the activation of the RAS/mammalian target of rapamycin (mTOR) cascades and RET crosstalk signaling, are now emerging as novel and potentially promising therapeutic treatments for aggressive MTC.

scholarly journals High Frequency Mutations of MYD88 and KMT2D in Chinese Chronic Lymphocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2761-2761 ◽  
Author(s):  
Shuhua Yi ◽  
Yuting Yan ◽  
Meiling Jin ◽  
Wenjie Xiong ◽  
Zengjun Li ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
High Frequency ◽  
Validation Cohort ◽  
Genetic Alterations ◽  
Lymphocytic Leukemia ◽  
Discovery Cohort ◽  
Similar Frequency ◽  
Western Population ◽  
Chi Squared ◽  
Treatment Naïve

Background: Chronic lymphocytic leukemia (CLL) is one of the most common forms of adult leukemia in the Western population but rare in Chinese descent. As Chinese CLL patients have distinct clinical features, higher frequency of mutated IGHV as well as unique BCR stereotype, we hypothesize that genetic alterations may contribute to the disease phenotype differences. We profiled the known recurrent mutated genes associated with Western CLLs in 338 Chinese CLL samples, with the goal to define the somatic mutation pattern in the Chinese CLL population. Methods: We first assessed 96 CLL mutated genes in a discovery cohort that includes 126 CLL samples using Illumina MiSeq platform. We then validated 20 recurrent mutated genes in a validation cohort that comprises of 212 CLL samples with Ion Torrent platform. The presence of mutation in DNA and mRNA were further validated by Sanger sequence. Results: A total of 303 untreated and 35 relapsed samples were investigated. The average sequencing depth was 1957X (range: 112 to 4254). In the discovery cohort, we identified recurrently mutated genes in TP53 (17.5%), SF3B1 (14.3%), ATM (13.7%), KMT2D (12.7%), MYD88 (10.3%), NOTCH1 (8.7%), FBXW7 (8.7%), BIRC3 (7.9%), POT1 (4.8%), KRAS (4.0%). This was further confirmed in the validation cohort. In comparison to the frequency of these mutations in the western studies, we observed an unexpected significantly higher frequency of mutations in MYD88 and KMT2D (Chi-squared test, p<0.01). Mutations of KMT2D occurred with a similar frequency in treatment-naïve (8%) and relapsed samples (9%). 19/30 (63%) mutations were loss-of-function as they are predicted to generate truncated proteins due to lacking part or all of the C-terminal domains (Figure 1A). We observed a significant co-occurrence between KMT2D mutations and trisomy 12 (Chi-squared test, p<0.01, Figure 1E), suggesting there could be intrinsic linkage between these lesions. Further integration with IGHV mutation status revealed that CLLs with KMT2D mutations were characterized by an overrepresentation of VH4-34 and VH4-39 (p<0.01, p=0.03, respectively) and enriched in stereotyped subset #8 (4/12, 33.3%) (Figure 1B). Consistent with previous reports that VH4-34 and VH4-39 are commonly used in Asians CLLs, we confirmed the high frequency of subset #8 in Chinese patients [1], indicating KMT2D as a uniquely mutated gene in Chinese CLLs. MYD88 mutations were found in 38/303 (13%) untreated CLLs. 17/38 (45%) of the mutations were at the L265P site (Figure 1C). Additional hotspot mutations were also detected (V217F 29%; S219C 13%). These mutations are associated with a significant male predominance (Chi-squared test, p<0.01), increased monoclonal gammopathy (15%, p=0.01), and a higher rate of Hepatitis B virus (HBV) infection (HBV core antibody positivity 56%, p=0.02). Most of these mutations (87%) were clonal and IGHV mutated (97%). It is worth to note that the usage of VH3-7 and VH4-34 were more dominant in patients with MYD88 V217F/S219C (6/16, 38%) and with L265P (6/17, 35%), respectively. Mutations of MYD88 are mutually exclusive with TP53 mutation and del(17p) (Chi-squared test, p<0.01). Moreover, we found a superior time to first treatment in MYD88-mutated patients compared with wide-type patients (Log-rank test, p=0.03). To further understand the linkage between mutations and clinical outcome, we divided 303 treatment-naive patients into two groups: Non-progressor (NPRO, 39%) and Progressor (PRO, 61%). NPRO and PRO were classified as patients who developed symptoms that need treatment either more than or less than three years after sampling. Epigenetic modifiers pathway mutations (KMT2D, CREBBP, EP300, TET2, ARID1A and IKZF1) were more frequently in PRO group (17% vs. 8%, p=0.02). Inflammatory pathway mutations (MYD88, BIRC3, CARD11 and TRAF3) was more involved in NPRO group, compared to PRO or Relapsed samples (21%, 15% and 0%, p<0.01). Conversely, DNA damage pathway mutations (TP53, ATM and POT1) was more frequently found in Relapsed and PRO groups compared to NPRO group (49%, 30% and 7%, p<0.01). Conclusion: In summary, we observed high frequency mutations in KMT2D and MYD88 that correlated with specific IGHV repertoire in Chinese CLL population. This suggests that pathogenesis of CLL between the Chinese and Western population may be different and potentially have therapeutic value. [1] Marinelli M, et al. Oncotarget. 2016 Apr 12;7(15):20520-31. Figure 1 Disclosures No relevant conflicts of interest to declare.

Protein-tyrosine Kinase p72 syk Is Activated by Platelet Activating Factor in Platelets

1994 ◽  
Vol 72 (06) ◽  
pp. 937-941 ◽  
Author(s):  
Karim Rezaul ◽  
Shigeru Yanagi ◽  
Kiyonao Sada ◽  
Takanobu Taniguchi ◽  
Hirohei Yamamura
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Kinase Assay ◽  
Potential Candidate ◽  
Protein Tyrosine ◽  
Induced Aggregation

SummaryIt has been demonstrated that activation of platelets by platelet-activating factor (PAF) results in a dramatic increase in tyrosine phosphorylation of several cellular proteins. We report here that p72 syk is a potential candidate for the protein-tyrosine phosphorylation following PAF stimulation in porcine platelets. Immunoprecipitation kinase assay revealed that PAF stimulation resulted in a rapid activation of p72 syk which peaked at 10 s. The level of activation was found to be dose dependent and could be completely inhibited by the PAF receptor antagonist, CV3988. Phosphorylation at the tyrosine residues of p72 syk coincided with activation of yllsyk. Pretreatment of platelets with aspirin and apyrase did not affect PAF induced activation of p72 syk .Furthermore, genistein, a potent protein-tyrosine-kinase inhibitor, diminished PAF-induced p72 syk activation and Ca2+ mobilization as well as platelet aggregation. These results suggest that p72 syk may play a critical role in PAF-induced aggregation, possibly through regulation of Ca2+ mobilization.

scholarly journals Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains

2021 ◽  
Vol 141 (3) ◽  
pp. 399-413 ◽  
Author(s):  
R. A. Hickman ◽  
P. L. Faust ◽  
M. K. Rosenblum ◽  
K. Marder ◽  
M. F. Mehler ◽  
...  
Keyword(s):  
New York ◽  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Validation Cohort ◽  
Hypothalamic Hamartoma ◽  
Discovery Cohort ◽  
Brain Bank ◽  
Neuronal Precursors ◽  
Neurodevelopmental Abnormalities ◽  
Developmental Malformations

AbstractNeuropathologic hallmarks of Huntington Disease (HD) include the progressive neurodegeneration of the striatum and the presence of Huntingtin (HTT) aggregates that result from abnormal polyQ expansion of the HTT gene. Whether the pathogenic trinucleotide repeat expansion of the HTT gene causes neurodevelopmental abnormalities has garnered attention in both murine and human studies; however, documentation of discrete malformations in autopsy brains of HD individuals has yet to be described. We retrospectively searched the New York Brain Bank (discovery cohort) and an independent cohort (validation cohort) to determine whether developmental malformations are more frequently detected in HD versus non-HD brains and to document their neuropathologic features. One-hundred and thirty HD and 1600 non-HD whole brains were included in the discovery cohort and 720 HD and 1989 non-HD half brains were assessed in the validation cohort. Cases with developmental malformations were found at 6.4–8.2 times greater frequency in HD than in non-HD brains (discovery cohort: OR 8.68, 95% CI 3.48–21.63, P=4.8 × 10-5; validation cohort: OR 6.50, 95% CI 1.83–23.17, P=0.0050). Periventricular nodular heterotopias (PNH) were the most frequent malformations and contained HTT and p62 aggregates analogous to the cortex, whereas cortical malformations with immature neuronal populations did not harbor such inclusions. HD individuals with malformations had heterozygous HTT CAG expansions between 40 and 52 repeats, were more frequently women, and all were asymmetric and focal, aside from one midline hypothalamic hamartoma. Using two independent brain bank cohorts, this large neuropathologic series demonstrates an increased occurrence of developmental malformations in HD brains. Since pathogenic HTT gene expansion is associated with genomic instability, one possible explanation is that neuronal precursors are more susceptible to somatic mutation of genes involved in cortical migration. Our findings further support emerging evidence that pathogenic trinucleotide repeat expansions of the HTT gene may impact neurodevelopment.

scholarly journals Identification BCL6 and miR-30 family associating with Ibrutinib resistance in activated B-cell-like diffuse large B-cell lymphoma

2021 ◽  
Vol 38 (4) ◽  
Author(s):  
Jiazheng Li ◽  
Yan Huang ◽  
Yun Zhang ◽  
Jingjing Wen ◽  
Yanxin Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Venn Diagram ◽  
Potential Candidate ◽  
Large B Cell Lymphoma ◽  
Ibrutinib Resistance ◽  
Large B Cell ◽  
Geo Database

AbstractIbrutinib has clear efficacy for activated B-cell-like diffuse large B cell lymphoma (ABC-DLBCL) in previous clinical researches. However, the resistance of Ibrutinib has limited its therapeutic benefit and the potential mechanism remains unclear. This study was aimed to identify potential candidate genes and miRNA targets to overcome Ibrutinib resistance in ABC-DLBCL. First, two expression profiles were downloaded from the GEO database, which used to identify the DEGs related to Ibrutinib resistance in ABC-DLBCL cell lines by GEO2R analysis separately. And the common DEGs were obtained though Venn diagram. Then Gene ontology (GO) and pathway enrichment analysis were conducted by DAVID database. From STRING database, BCL6, IL10, IL2RB, IRF4, CD80, PRDM1and GZMB were determined to be the hub genes by protein–protein interaction (PPI) network. Through miRNA-mRNA targeting network, we found that BCL6, IRF4, CD80, and PRDM1 were common target genes of miR-30 family. The cBioPortal database showed that BCL6 had the highest level of genetic alterations among DLBCL. In addition, another expression profile from GEO database showed that BCL6 was significantly high expression in no responsive patients after Ibrutinib treatment, and the receiver operating characteristic (ROC) curve which was used to evaluate the relationship between BCL6 expression and its effect was 0.67. MTT assay showed that treatment with FX1 (a BCL6 inhibitor) can enhance the sensitivity of Ibrutinib in C481S BTK HBL-1 cells. The results suggested that BCL6 and miR-30 family maybe associate with Ibrutinib resistance in ABC-DLBCL.

Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3958-3961 ◽  
Author(s):  
Jörg Cammenga ◽  
Stefan Horn ◽  
Ulla Bergholz ◽  
Gunhild Sommer ◽  
Peter Besmer ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Extracellular Domain ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Core Binding Factor ◽  
Kit Receptor ◽  
Binding Factor

Multiple genetic alterations are required to induce acute myelogenous leukemia (AML). Mutations in the extracellular domain of the KIT receptor are almost exclusively found in patients with AML carrying translocations or inversions affecting members of the core binding factor (CBF) gene family and correlate with a high risk of relapse. We demonstrate that these complex insertion and deletion mutations lead to constitutive activation of the KIT receptor, which induces factor-independent growth of interleukin-3 (IL-3)–dependent cells. Mutation of the evolutionary conserved amino acid D419 within the extracellular domain was sufficient to constitutively activate the KIT receptor, although high expression levels were required. Dose-dependent growth inhibition and apoptosis were observed using either the protein tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) or by blocking the phosphoinositide-3-kinase (PI3K)–AKT pathway. Our data show that the addition of kinase inhibitors to conventional chemotherapy might be a new therapeutic option for CBF-AML expressing mutant KIT.

scholarly journals Registered report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Vidhu Sharma ◽  
Lisa Young ◽  
Miguel Cavadas ◽  
Kate Owen ◽  
Keyword(s):  
Cancer Biology ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Single Agent ◽  
Braf Inhibitor ◽  
Open Science ◽  
Mek Inhibitors ◽  
Erk Phosphorylation ◽  
Erk Activity ◽  
A375 Cells

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (<xref ref-type="bibr" rid="bib4">Errington et al., 2014</xref>). This Registered Report describes the proposed replication plan of key experiments from “COT drives resistance to RAF inhibition through MAPK pathway reactivation” by Johannessen and colleagues, published in Nature in 2010 (<xref ref-type="bibr" rid="bib10">Johannessen et al., 2010</xref>). The key experiments to be replicated are those reported in Figures 3B, 3D-E, 3I, and 4E-F. In Figures 3B, D-E, RPMI-7951 and OUMS023 cells were reported to exhibit robust ERK/MEK activity concomitant with reduced growth sensitivity in the presence of the BRAF inhibitor PLX4720. MAP3K8 (COT/TPL2) directly regulated MEK/ERK phosphorylation, as the treatment of RPMI-7951 cells with a MAP3K8 kinase inhibitor resulted in a dose-dependent suppression of MEK/ERK activity (Figure 3I). In contrast, MAP3K8-deficient A375 cells remained sensitive to BRAF inhibition, exhibiting reduced growth and MEK/ERK activity during inhibitor treatment. To determine if RAF and MEK inhibitors together can overcome single-agent resistance, MAP3K8-expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone, as reported in Figures 4E-F. The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.

scholarly journals Identification of gut microbiome markers for schizophrenia delineates a potential role of Streptococcus

2019 ◽  
Author(s):  
Feng Zhu ◽  
Yanmei Ju ◽  
Wei Wang ◽  
Qi Wang ◽  
Ruijin Guo ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Validation Cohort ◽  
Bacterial Species ◽  
Metagenomic Sequencing ◽  
Operating Characteristics ◽  
Discovery Cohort ◽  
Peripheral Tissues ◽  
Functional Changes ◽  
Microbial Biomarkers

AbstractEmerging evidence has linked the gut microbiota to schizophrenia. However, the functional changes in the gut microbiota and the biological role of individual bacterial species in schizophrenia have not been explored systematically. Here, we characterized the gut microbiota in schizophrenia using shotgun metagenomic sequencing of feces from a discovery cohort of 90 drug-free patients and 81 controls, as well as a validation cohort of 45 patients taking antipsychotics and 45 controls. We screened 83 schizophrenia-associated bacterial species and constructed a classifier comprising 26 microbial biomarkers that distinguished patients from controls with a 0.896 area under the receiver operating characteristics curve (AUC) in the discovery cohort and 0.765 AUC in the validation cohort. Our analysis of fecal metagenomes revealed that schizophrenia-associated gut–brain modules included short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters including glutamate, γ-aminobutyric acid, and nitric oxide. The schizophrenia-enriched gut bacterial species include several oral cavity-resident microbes, such as Streptococcus vestibularis. We transplanted Streptococcus vestibularis into the gut of the mice with antibiotic-induced microbiota depletion to explore its functional role. We observed that this microbe transiently inhabited the mouse gut and this was followed by hyperactivity and deficit in social behaviors, accompanied with altered neurotransmitter levels in peripheral tissues. In conclusion, our study identified 26 schizophrenia-associated bacterial species representing potential microbial targets for future treatment, as well as gut–brain modules, some of which may give rise to new microbial metabolites involved in the development of schizophrenia.

scholarly journals Circulating microRNA Expression in Cushing’s Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Sharmilee Vetrivel ◽  
Ru Zhang ◽  
Mareen Engel ◽  
Barbara Altieri ◽  
Leah Braun ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Validation Cohort ◽  
Cushing's Syndrome ◽  
Circulating Microrna ◽  
High Morbidity ◽  
Discovery Cohort ◽  
Serum Samples ◽  
Curative Surgery ◽  
Before And After ◽  
Diagnosis And Classification

ContextCushing’s syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging.ObjectiveCirculating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes.MethodsWe included three groups of patients from the German Cushing’s registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing’s Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls.ResultsNGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression.OutcomeIn conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.

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