CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant

Ikeya, Akira; Nakashima, Mitsuko; Yamashita, Miho; Kakizawa, Keisuke; Okawa, Yuta; Saitsu, Hirotomo; Sasaki, Shigekazu; Sasano, Hironobu; Suda, Takafumi; Osuga, Yutaka

doi:10.1371/journal.pone.0231665

Cited by 10 publications

(11 citation statements)

References 59 publications

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“…Borges et al observed more aggressive disease in tumors with overexpression of AURKA and AURKB and presumed that the inhibition of these proteins could be a promising approach for the treatment for ACC [ 26 ] by using Aurora-specific degraders [ 138 ]. However, only in vitro data exist thus far [ 139 , 140 ]. Lira et al [ 123 ] discussed IGF1R inhibition as a possible target, but the in vitro data were not convincing [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Adrenocortical Carcinoma in Childhood: A Systematic Review

Riedmeier¹,

Decarolis

Haubitz³

et al. 2021

Cancers

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Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89%). Most patients were diagnosed with localized disease, whereas 23% had metastasis at primary diagnosis. Only 72% of the patients achieved complete resection. In 334 children (23%), recurrent disease was reported: 81%—local recurrence, 19% (n = 65)—distant metastases at relapse. Patients <4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Adrenocortical Carcinoma in Childhood: A Systematic Review

Riedmeier¹,

Decarolis

Haubitz³

et al. 2021

Cancers

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show abstract

“…In the past few years, the overexpression of CCNB2 in tumor tissues has been shown to be an unfavorable prognostic biomarker in many human cancers, including gastric cancer, 22 breast cancer, 23 pituitary adenoma, 24 nasopharyngeal carcinoma, 25 and adrenocortical carcinoma. 26 The results of bioinformatics analysis showed that mRNA expression of CCNB2 was significantly associated with TNBC patients’ prognosis. Owing to the small sample size of TNBC, this study has certain limitations.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of CCNB2 Expression in Triple-Negative Breast Cancer

Cao¹,

Sun²,

Min³

et al. 2021

CMAR

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Purpose The aim of this study was to explore potential gene therapy targets for triple-negative breast cancer (TNBC). Patients and Methods Three gene expression profiles (GSE64790, GSE62931, and GSE38959) from the Gene Expression Omnibus (GEO) database were analyzed. The GEO2R analysis tool was used to screen for differentially expressed genes (DEGs) between TNBC and normal tissues, followed by Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the DEGs. The protein–protein interaction network of DEGs was visualized using Metascape to identify the core genes. Subsequently, transcriptional data for the core genes in patients with breast cancer were investigated in the ONCOMINE database. Kaplan–Meier survival analysis was used to evaluate the prognostic value of core gene expression levels in patients with TNBC. Finally, the clinicopathological and long-term follow-up data of 39 patients with TNBC were retrospectively analyzed at the First Affiliated Hospital of the Bengbu Medical College between January 2014 and July 2020. Immunohistochemistry was used to evaluate the expression and subcellular localization of CCNB2 in TNBC tissues. Results A total of 66 DEGs were identified between TNBC and normal tissues, including 33 upregulated and 33 downregulated genes in TNBC. Furthermore, a potential protein complex was identified for five core genes. The high expression of these core genes, especially the overexpression of CCNB2 , was correlated with a poor prognosis of patients with TNBC. The CCNB2 protein was expressed in the cytoplasm, and its expression was significantly higher in TNBC tissues than that in the adjacent nontumor tissues. Overall survival of patients was significantly correlated with the expression of CCNB2 ( p < 0.05). Conclusion CCNB2 may play a crucial role in the development of TNBC and has the potential to be used as a prognostic biomarker for TNBC.

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“…Preliminary clinical studies have been conducted to validate the efficacy and safety of Aurora kinase inhibitors in AML [ 48 – 50 ]. Although the association of TP53 mutation and AURKA expression has been rarely studied previously for AML, it was explored in solid tumors with high frequency of TP53 variants, including adrenocortical carcinoma [ 51 ], pancreatic cancer [ 52 ], head and neck cancer [ 53 ], hepatocellular carcinoma [ 54 ] and ovarian cancer [ 55 ]. Moreover, in cancer cell lines lacking p53, resulting from genetic engineering to express HPV16-E6 oncoprotein or siRNA targeting TP53, the inhibitor of Aurora kinases (VX680) induced apoptosis was enhanced in comparison with cell lines with wide-type p53 [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

The landscape of gene co-expression modules correlating with prognostic genetic abnormalities in AML

Guo

Gao

et al. 2021

J Transl Med

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Background The heterogenous cytogenetic and molecular variations were harbored by AML patients, some of which are related with AML pathogenesis and clinical outcomes. We aimed to uncover the intrinsic expression profiles correlating with prognostic genetic abnormalities by WGCNA. Methods We downloaded the clinical and expression dataset from BeatAML, TCGA and GEO database. Using R (version 4.0.2) and ‘WGCNA’ package, the co-expression modules correlating with the ELN2017 prognostic markers were identified (R2 ≥ 0.4, p < 0.01). ORA detected the enriched pathways for the key co-expression modules. The patients in TCGA cohort were randomly assigned into the training set (50%) and testing set (50%). The LASSO penalized regression analysis was employed to build the prediction model, fitting OS to the expression level of hub genes by ‘glmnet’ package. Then the testing and 2 independent validation sets (GSE12417 and GSE37642) were used to validate the diagnostic utility and accuracy of the model. Results A total of 37 gene co-expression modules and 973 hub genes were identified for the BeatAML cohort. We found that 3 modules were significantly correlated with genetic markers (the ‘lightyellow’ module for NPM1 mutation, the ‘saddlebrown’ module for RUNX1 mutation, the ‘lightgreen’ module for TP53 mutation). ORA revealed that the ‘lightyellow’ module was mainly enriched in DNA-binding transcription factor activity and activation of HOX genes. The ‘saddlebrown’ module was enriched in immune response process. And the ‘lightgreen’ module was predominantly enriched in mitosis cell cycle process. The LASSO- regression analysis identified 6 genes (NFKB2, NEK9, HOXA7, APRC5L, FAM30A and LOC105371592) with non-zero coefficients. The risk score generated from the 6-gene model, was associated with ELN2017 risk stratification, relapsed disease, and prior MDS history. The 5-year AUC for the model was 0.822 and 0.824 in the training and testing sets, respectively. Moreover, the diagnostic utility of the model was robust when it was employed in 2 validation sets (5-year AUC 0.743–0.79). Conclusions We established the co-expression network signature correlated with the ELN2017 recommended prognostic genetic abnormalities in AML. The 6-gene prediction model for AML survival was developed and validated by multiple datasets.

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CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant

Cited by 10 publications

References 59 publications

Adrenocortical Carcinoma in Childhood: A Systematic Review

Adrenocortical Carcinoma in Childhood: A Systematic Review

Prognostic Significance of CCNB2 Expression in Triple-Negative Breast Cancer

The landscape of gene co-expression modules correlating with prognostic genetic abnormalities in AML

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