Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from cirrhosis and HCC tissue samples

ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most-common cancer worldwide causing nearly 600,000 deaths esch year. Approximately 80% of HCC develops on the background of cirrhosis.It is necessary to identify novel genes involved in HCC to implement new diagnostic and treatment options. However, the molecular pathogenesis of HCC largely remains unsolved. Only a few genetic alterations, namely those affecting p53, β-catenin and p16INK4a have been implicated at moderate frequencies of these cancers. Early detection of HCC with appropriate treatment can decrease tumor-related deaths We used microarrays to detail the global programme of gene expression profiles of cirrhosis and tumor liver samples. 15 cirrhosis and 15 HCC samples were collected with informed constent of each patient. Surgically resected tissues were snap frozen in liquid nitrogen and stored at -80C, and subjected to RNA extraction. Histology slides were prepared for all samples and scored by an experienced scientist. For the tumor samples, tissues were resected from inside the tumor, while tissues were resected from adjacent tissue sorrounding the tumor for non-tumor samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Mehmet Ozturk

PROVIDER: E-GEOD-17548 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

Yildiz Gokhan G Arslan-Ergul Ayca A Bagislar Sevgi S Konu Ozlen O Yuzugullu Haluk H Gursoy-Yuzugullu Ozge O Ozturk Nuri N Ozen Cigdem C Ozdag Hilal H Erdal Esra E Karademir Sedat S Sagol Ozgul O Mizrak Dilsa D Bozkaya Hakan H Ilk Hakki Gokhan HG Ilk Ozlem O Bilen Biter B Cetin-Atalay Rengul R Akar Nejat N Ozturk Mehmet M

PloS one 20130515 5

Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by g ...[more]

PMID: 23691139

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Project description:Background and Aims Formalin-fixed, paraffin-embedded (FFPE) tissue is the most commonly available form of archived clinical specimens, which are often stored as thin sections on glass slides. RNA isolated from such archived section (AS) of FFPE tissue is more degraded compared to freshly cut (FC) FFPE section because of prolonged air exposure. In this study, we evaluated performance of transcriptome profiling-based disease classification in AS-FFPE tissue. Methods Genome-wide gene-expression profiles of AS-FFPE tissues of 83 hepatocellular carcinoma (HCC) and 47 liver cirrhosis samples were generated by using whole-genome DASL assay (Illumina), and compared with the profiles previously produced by using FC tissue sections from the same FFPE blocks. Quality of the profiles and performance of gene signature-based class prediction were systematically evaluated. Results RNA quality and assay reproducibility of AS-FFPE RNA were comparable to intermediate ~ poor quality FC-FFPE samples (R2 as high as 0.93). Gene-expression signal was detected in lower number of probes in AS FFPE samples compared to FC-FFPE samples (proportion of probes with present signal (%P-call): 10%~60% and 70%~90% in AS- and FC-FFPE profiles, respectively). Based on %P-call quality threshold of 20%, 64/88 (77%) HCC and 37/48 (77%) liver profiles were judged as having relatively good quality data with comparable inter-sample correlation. Inter-sample correlation coefficient, as a measure to detect outlier profiles due to poor RNA quality, was also lower in AS-FFPE (0.4~0.9) compared to FC-FFPE (0.6~1.0). In the genome-wide profiling analysis, previously identified molecular subclasses of HCC tumors were reproduced in 67/83 (81%) samples, which was improved to 43/48 (90%) samples when we focused on statistically confident predictions (p<0.05). A 186-gene prognostic signature in liver cirrhosis was reproduced in 32/47 (68%) samples, which was slightly improved to 11/16 (69%) when focused on statistically significant predictions. Conclusions We observed decay of genome-wide transcriptional profiles in AS-FFPE tissues in quantitative manner. However, disease classification was still possible, which suggests potential of AS-FFPE material for clinical diagnosis and prognosis. FFPE tissue sections (10 micron-thick) sliced from 5~16-year-old FFPE blocks and archived for 6~7 years on glass slide Gene-expression profiles of archived section of formalin-fixed paraffin-embedded (AS-FFPE) liver tissues from HCC patients: 47 samples Gene-expression profiles of archived section of formalin-fixed paraffin-embedded (AS-FFPE) tumor tissues from HCC patients: 83 samples

Project description:Background & Aims: Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. Methods: We analyzed gene expression profiles of non-tumor liver tissues from 392 patients with early-stage HCC (training set, n=167 and validation set, n=225) and liver tissue from patients with cirrhosis without HCC (n=216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of N-nitrosodiethylamine followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then given orally the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, given orally aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. Results: We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of non-tumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor beta signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% 1.21–4.80). Mice with chemically-induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel downregulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. Conclusions: We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that associates with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and developed fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis. To assess the impact of sulindac or aspirin/clopidogrel treatment on the immune-mediated cancer field, we collected samples from a choline-deficient high-fat diet fed mouse model developing NASH, HCC and fibrosis, previously published (Malehmir M et al, Nat Med, 2019) . We analyzed gene expression profiling of non-tumor liver samples from mice fed a CD-HFD for 12 weeks treated with vehicle that presented HCC and fibrosis (considered as high-risk group) (n=4); as well as mice fed a CD-HFD for 12 weeks treated with sulindac (n=10) or aspirin/clopidogrel (n=6). As controls, we analyzed samples from mice fed a chow-diet for 12 weeks (considered as healthy group) (n=5).

Dataset Information

Expression data from cirrhosis and HCC tissue samples

Publications

Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

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