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Long non-coding RNA expression profiling reveals LINC00271 as a prognostic marker in adrenocortical carcinoma

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124531 | GEO | 2019/07/01

REPOSITORIES: GEO

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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:Objective: Globally, esophageal cancer is among the most deadly cancer forms. Long non-coding RNAs (lncRNA) are frequently found to have important regulatory roles. We aim to assess the lncRNA expression profile of esophageal squamous cell carcinoma (ESCC) and identify prognosis related lncRNAs. Design: LncRNA expression profiles were studied by microarray in paired tumor and normal tissues from 119 ESCC patients, and validated by qRT-PCR. The 119 patients were subsequently divided randomly into training (n=60) and test (n=59) groups. A prognostic signature was developed from the training group using a random forest supervised classification algorithm and a nearest shrunken centroid algorithm, and validated in test group and further in an independent cohort (n=60). The independence of the signature in survival prediction was evaluated by Multivariable Cox regression analysis. Results: LncRNAs showed significantly altered expression in ESCC tissues. From the training group, we identified a three-lncRNA signature (including the lncRNAs ENST00000435885•1, XLOC_013014, and ENST00000547963•1) which classified the patients into two groups with significantly different overall survival (median survival 19•2 months vs. not reached, p<0•0001). The signature was applied to the test group (median survival 21•5 months vs. not reached, p=0•0030) and independent cohort (median survival 25•8 months vs. not reached, p=0•0187) and showed similar prognostic values in both. Multivariable Cox regression analysis showed that the signature was an independent prognostic factor for ESCC patients. Stratified analysis suggested that the signature was prognostic within clinical stages. Conclusions: Our results suggest that the three-lncRNA signature can serve as a novel biomarker for the prognosis of ESCC patients. Application of it allows for more accurate survival prediction. The lncRNA expression profiles of cancer and adjacent normal tissues form 119 ESCC patients were studied by microarray and an lncRNA signature that can perdict the survival of ESCC patients was identified.

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Long non-coding RNA expression profiling reveals LINC00271 as a prognostic marker in adrenocortical carcinoma

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