Project description:Background: Adrenal myelolipoma (AML) is a relatively common and invariably benign tumor composed of adipose tissue and hematopoietic elements. Due to the variable proportion of fat and hematopoietic elements, it is sometimes challenging to differentiate AML from adrenocortical carcinoma (ACC). MicroRNAs have been identified as promising biomarkers in many tumors, including adrenocortical neoplasms, but the microRNA expression of adrenal myelolipoma has not been investigated, yet. Aims: To perform a large scale microRNA expression profiling in adrenal myelolipoma, benign and malignant adrenocortical tumors to identify potential microRNA biomarkers. Methods: Next-generation sequencing (NGS) on 30 formalin-fixed paraffin-embedded archived tissue samples (discovery cohort: 10 adrenocortical adenoma (ACA), 10 ACC and 10 myelolipoma) was performed by Illumina MiSeq. Significantly differentially expressed microRNAs were validated by real-time RT-qPCR in an independent validation cohort comprised of 10 ACA, 10 myelolipoma and 9 ACC samples. Results: We have found relative overexpression of miR- 451a, miR-486-5p, miR-363-3p and miR-150-5p in myelolipoma compared to the other two tumor groups by NGS. For ACC, we have found up-regulation of miR-184, miR-483-5p, miR-431-5p and miR-183-5p compared to myelolipoma and ACA. Validation by RT-qPCR, confirmed significant overexpression of miR-451a, miR-486-5p and miR-150-5p in myelolipomas relative to ACA and ACC, whereas significant overexpression of miR-184 and miR-183-5p was confirmed in ACC relative to the other 2 groups. The overexpression of miR-483-5p has not turned out to be significant in ACC relative to myelolipomas in the validation cohort. Conclusions: Overexpressed miR-451a, miR-486-5p and miR-150-5p might be potential tissue markers of adrenal myelolipoma. The lack of significance in the expression of miR-483-5p between ACC and myelolipoma is remarkable, as miR-483-5p has been considered to be the best marker of adrenal malignancy to date.

Project description:The molecular pathogenesis of adrenocortical diseases, particularly adrenocortical carcinoma (ACC), has advanced considerably in recent years due to the application of high-throughput molecular analysis. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) offers an approach for identifying and quantifying numerous proteins in biological samples. Aiming to identify differences in adrenal cortex disease protein signatures that may contribute to understanding their distinct pathogenesis, we used LC-MS/MS and bioinformatics analysis to compare the proteomic profiles of normal human adrenal samples (NHA), adrenocortical adenomas (ACA), adrenocortical carcinomas (ACC), and primary macronodular adrenocortical hyperplasia (PMAH) tumor samples, with (w) and without (wt) ARMC5 mutation. A total of 7,350 proteins were identified, with 3,976 proteins quantified in all analyzed samples, and differentially expressed proteins (DEPs) noted as upregulated and downregulated were highlighted as relevant. We identified 27 DEPs in ACA vs. NHA, where MT3 and RBM3 are upregulated, and NEFL, HAAO, SOD3, IGHA2, and HDGFL3 are the top five of 25 downregulated proteins; 49 DEPs in ACC vs. NHA, with DEFA3, NUP160, SRRM2, and RBM3 upregulated, alongside SOD3, CNRIP, DNAH1, GAMT, ADIRF, and CA3 as the top six of 45 downregulated proteins; 81 DEPs in PMAH vs. NHA, with RBM3, RIGI, SPAG9, and SRRM2 proteins as the top four of 9 upregulated proteins, and 72 downregulated proteins with AFM, CA 3, IGKV1-5, ADIRF, and LRG1 as the top five; ACC vs. ACA identified 64 upregulated and 48 downregulated DEPs, with PHGDH (SERA), PDCD4, MAGED2, ERAP2, FTO, DUSP23, UBLCP 1, NSUN2, TP53BP1, NUP107 as the top ten upregulated, and RMDN2, CSRP1, ACAD11, PACSIN3, HAGH (GLO2), ALG5, NEXN, ABLIM1, LBP, and SYNPO2 as the top ten downregulated in ACC. DEPs analysis in PMAHw vs. PMAHwt showed the lowest number of DEPs, with NOSTRIN, PCP4, C4 BPB, and SERB (PSPH) as the top four of 12 upregulated proteins, and 4 downregulated proteins EST2 (TERT), PNPT1, RDH13, and STAB1 in PMAHw. Comparative analysis highlighted several targets for functional analysis and validation to determine the mechanism of action and protein biomarkers.

Project description:Adrenocortical carcinoma (ACC) is an aggressive malignancy with a low but variable overall survival rate. Even after complete tumor resection, over half of patients develop recurrent disease. Long noncoding RNAs (lncRNAs) have been found to be involved in cancer initiation/progression and as markers of cancer prognosis. The role of lncRNAs in ACC is poorly understood. Thus, in this study we performed lncRNA expression profiling in ACC, adrenocortical adenoma (ACA) and normal adrenal cortex (NAC). Total RNA was extracted from fresh frozen tissue samples (11 ACA, nine ACC and five NAC samples) with histopathological confirmed diagnosis. ArrayStar Human LncRNA/mRNA Expression Microarray V3.0 was used for transcriptome analysis. Differentially expressed lncRNAs were validated using TaqMan real-time quantitative PCR in a validation cohort including an additional 10 ACCs. The ACC dataset from the Cancer Genome Atlas (TCGA) project was used to evaluate the prognostic utility of lncRNAs found to be differentially expressed in ACC. Survival curves were plotted by Kaplan-Meier analysis, and differences in survival rates were assessed using a log-rank test. P < 0.05 was considered significant. Gene Set Enrichment Analysis (GSEA) was performed to identify lncRNA-associated biological signaling pathways. Unsupervised hierarchical and heat map clustering showed distinct clustering of ACC samples compared with NAC and ACA samples by lncRNA expression profiles. A total of 874 lncRNAs were differentially expressed between ACC and NAC, including known carcinogenesis-related lncRNAs such as HOTTIP, HOXA11-AS1, CRNDE, LINC00271 and TBXAS1. One thousand seventy-six lncRNAs were differentially expressed between ACC and ACA. LINC00271 was a prognostic marker, with patients with low LINC00271 expression surviving significantly shorter than patients with a high LINC00271 expression. Median survival time (MST) for the low-expression group was 1788 days, whereas the MST was not reached for the high-expression group (P < 0.019). Importantly, low LINC00271 expression was positively associated with WNT signaling, cell cycle, chromosome segregation and tissue morphogenesis pathways. ACC has a distinct lncRNA expression profile. LINC00271 is a prognostic marker in ACC and is involved in biological pathways commonly dysregulated in ACC.

Project description:Adrenocortical carcinoma (ACC) is a rare endocrine malignancy accounting for between 0.02 and 0.2 percent of all cancer deaths. Surgical removal offers the only current potential for cure. Unfortunately, ACC has undergone metastatic spread in approximately 40-70 percent of patients at the time of diagnosis. Standard chemotherapy with mitotane containing regimens is often ineffective and associated with intolerable side-effects. Modern molecular technologies now allow the examination of germ-line and somatic DNA for chromosomal alterations which can give biological insight into cancer processes. Using an array-based high density comparative genomic hybridization (CGH) screen, genomic aberrations within 25 ACC patients were assessed to identify genomic characteristic of this cancer. Genomes were queried with >44,000 probes on the Agilent Human Genome CGH array detecting regions of chromosomal gain and loss within the tumor population. Statistical analysis of this genetic landscape reveals a set of chromosomal aberrations strongly associated with survival in an accumulation dependent fashion. These regions may hold prognostic indicators and offer therapeutic targets that can be used to develop novel treatments for aggressive tumors. Experiment Overall Design: Array-based high density comparative genomic hybridization (CGH) screen was utilized to identify genomic aberrations within 25 ACC patients. Thirteen tumor samples are from male and 12 are from female patients. The mean age of patients is 51.8 years (range, 23.3-77.7 years) with a median of 54.2 years. The mean tumor physical measurements for the ACC set are a mean weight of 536.3 grams (range, 20.5-2880 grams) and size of 10.7 cm (range, 3-21.5 cm). The clinical data also includes functional status of the tumor which is based on clinical parameters and confirmed by biochemical analysis. Nonfunctional tumors or those that do not over-produce hormones represent 48% of the tumor set. The localization of each tumor is a measure of the tumor metastatic characteristic at time of operation while tumor grade is a histologically based rating system for tumor progression. Sixty percent of the tumors (15 of 25) were localized to the adrenal area with no indication of metastatic spread. The majority of tumors were grade 3 and 4 at time of diagnosis (17 of 25) indicating necrosis and atypical mitosis of >21/50 hpf. Genomes were queried with >44,000 probes on the Agilent Human Genome CGH array detecting regions of chromosomal gain and loss within the tumor population.

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Genome-scale methylome profiling of adrenocortical carcinomas (ACC) and adenomas (ACA)

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