Genomic and Epigenomic Features of Primary and Recurrent Hepatocellular Carcinomas
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PROVIDER: EGAS00001002094 | EGA |
REPOSITORIES: EGA
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Project description:BackgroundEpigenome-wide studies in hepatocellular carcinoma (HCC) have identified numerous genes with aberrant DNA methylation. However, methods for triaging functional candidate genes as useful biomarkers for epidemiological study have not yet been developed.MethodsWe conducted targeted next-generation bisulfite sequencing (bis-seq) to investigate associations of DNA methylation and mRNA expression in HCC. Integrative analyses of epigenetic profiles with DNA copy number analysis were used to pinpoint functional genes regulated mainly by altered DNA methylation.ResultsSignificant differences between HCC tumor and adjacent non-tumor tissue were observed for 28 bis-seq amplicons, with methylation differences varying from 12% to 43%. Available mRNA expression data in Oncomine were evaluated. Two candidate genes (GRASP and TSPYL5) were significantly under-expressed in HCC tumors in comparison with precursor and normal liver tissues. The expression levels in tumor tissues were, respectively, 1.828 and - 0.148, significantly lower than those in both precursor and normal liver tissue. Validations in an additional 42 paired tissues showed consistent under-expression in tumor tissue for GRASP (-7.49) and TSPYL5 (-9.71). A highly consistent DNA hypermethylation and mRNA repression pattern was obtained for both GRASP (69%) and TSPYL5 (73%), suggesting that their biological function is regulated by DNA methylation. Another two genes (RGS17 and NR2E1) at Chr6q showed significantly decreased DNA methylation in tumors with loss of DNA copy number compared to those without, suggesting alternative roles of DNA copy number losses and hypermethylation in the regulation of RGS17 and NR2E1.ConclusionsThese results suggest that integrative analyses of epigenomic and genomic data provide an efficient way to filter functional biomarkers for future epidemiological studies in human cancers.
| S-EPMC4460673 | biostudies-literature
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| EGAS00001002463 | EGA
Project description:Understanding the intratumoral heterogeneity of hepatocellular carcinoma is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 hepatocellular carcinoma cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions, that is, located on the "trunk" of the evolutionary tree. In addition, we found that variants within several drug targets such as KIT, SYK, and PIK3CA were mutated in a fully clonal manner, indicating their therapeutic potentials for hepatocellular carcinoma. Temporal dissection of mutational signatures suggested that mutagenic processes associated with exposure to aristolochic acid and aflatoxin might play a more important role in early, as opposed to late, stages of hepatocellular carcinoma development. Moreover, we observed extensive intratumoral epigenetic heterogeneity in hepatocellular carcinoma based on multiple independent analytical methods and showed that intratumoral methylation heterogeneity might play important roles in the biology of hepatocellular carcinoma cells. Our results also demonstrated prominent heterogeneity of intratumoral methylation even in a stable hepatocellular carcinoma genome. Together, these findings highlight widespread intratumoral heterogeneity at both the genomic and epigenomic levels in hepatocellular carcinoma and provide an important molecular foundation for better understanding the pathogenesis of this malignancy. Cancer Res; 77(9); 2255-65. ©2017 AACR.
| S-EPMC5413372 | biostudies-literature
Project description:Comparison of expression profiles of primary colorectal cancers with liver metastases of the same patient. Additionally, expression data of normal colon and liver tissue. Abstract of publication will be included upon publication Keywords: expression profiling, colorectal cancer, colon cancer, liver metastasis, normal colonic tissue, normal liver tissue
2010-07-07 | GSE14297 | GEO
Project description:Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.
| S-EPMC7303129 | biostudies-literature
Project description:To delineate gene expression levels in whole non-metastatic and metastatic transplantable primary mouse mammary tumour allografts Abstract to be provided from publication
2013-01-01 | GSE42272 | GEO
Project description:Hepatocellular carcinoma (HCC) is a prevalent malignancy cancer worldwide with a poor prognosis. Hepatic resection is indicated as a potentially curative option for HCC patients in the early stage. However, due to multiple nodules, it leads to clinical challenges for surgical management. Approximately 41%-75% of HCC cases are multifocal at initial diagnosis, which may arise from multicentric occurrence (MO-HCC) or intrahepatic metastasis (IM-HCC) pattern with significantly different clinical outcomes. Effectively differentiating the two mechanisms is crucial to prioritize the allocation of surgery for multifocal HCC. In this study, we collected a multifocal hepatocellular carcinoma cohort of 17 patients with a total of 34 samples. We performed whole-exome sequencing and staining of pathological HE sections for each lesion. Reconstruction of the clonal evolutionary pattern using genome mutations showed that the intrahepatic metastogenesis pattern had a poorer survival performance than independent origins, with variants in the TP53, ARID1A, and higher CNV variants occurring more significantly in the metastatic pattern. Cross-modality analysis with pathology showed that molecular classification results were consistent with pathology results in 70.6% of patients, and we found that pathology results could further complement the classification for undefined patterns of occurrence. Based on these results, we propose a model to differentiate the pattern of multifocal hepatocellular carcinoma based on the pathological results and genome mutations information, which can provide guidelines for diagnosing and treating multifocal hepatocellular carcinoma.
| S-EPMC9251469 | biostudies-literature
Project description:The tumor heterogeneity between the primary and recurrent hepatocellular carcinoma (HCC) has rarely been explored. The present study aims to illustrate the heterogeneity between the primary and recurrent tumors by integrating multiomic analyses.
2023-01-06 | GSE164359 | GEO
Project description:Tremendous efforts have been made to explore biomarkers for classification and grading on gliomas. The goal of this study was to identify more molecular features that are associated with clinical outcomes by comparing the genomic profiles of primary and recurrent gliomas and determine potential recurrence leading factors that are significantly enriched in relapse tumors. Hybrid capture based next generation sequencing (NGS) analysis was performed on 64 primary and 17 recurrent glioma biopsies. Copy number variation (CNV) was more frequent in recurrent tumors and CDKN2A/B loss was significantly enriched. In addition, overall mutations in cell cycle pathway are more common in relapse tumors. The patterns of gene sets, including IDH1/TERT and IDH1/TP53 exhibited significant difference between the groups. Survival analysis uncovered the worse disease-free survival (DFS) and overall survival (OS) associated with altered copy number and excessive activation of CELL CYCLE pathway. High Tumor Mutation Burden (TMB) was also a biomarker with great potential for poor prognosis. The assessment of genomic characteristics in primary versus recurrent gliomas aids the discovery of potential predictive biomarkers. The prognostic value of TMB in gliomas was raised for the first time.
| S-EPMC6831607 | biostudies-literature
Project description:The tumor heterogeneity between the primary and recurrent hepatocellular carcinoma (HCC) has rarely been explored. The present study aims to illustrate the heterogeneity between the primary and recurrent tumors by integrating multiomic analyses.
2021-03-18 | PXD024810 |