Dataset Information

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

ABSTRACT: Adenoid cystic carcinomas (ACCs) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole genome sequencing, expression and pathway analyses. In addition to the well-described MYB-NFIB fusion which was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95%CI=41Ã¢Â€Â“77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (p=0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared to those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.

PROVIDER: EGAS00001002812 | EGA |

REPOSITORIES: EGA

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Publications

The influence of stimulus movements on perception in parafoveal stabilized vision.

Gerrits H J HJ Vendrik A J AJ

Vision research 19740201 2

PMID: 4818686

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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.

Dataset Information

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Publications

The influence of stimulus movements on perception in parafoveal stabilized vision.

Similar Datasets

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