Abstract
BackgroundGene silencing due to aberrant DNA methylation is a frequent event in hepatocellular carcinoma (HCC) and also in hepatocellular adenoma (HCA). However, very little is known about epigenetic defects in fibrolamellar carcinoma (FLC), a rare variant of hepatocellular carcinoma that displays distinct clinical and morphological features.Methodology/Principal FindingsWe analyzed the methylation status of the APC, CDH1, cyclinD2, GSTπ1, hsa-mir-9-1, hsa-mir-9-2, and RASSF1A gene in a series of 15 FLC and paired normal liver tissue specimens by quantitative high-resolution pyrosequencing. Results were compared with common HCC arising in non-cirrhotic liver (n = 10). Frequent aberrant hypermethylation was found for the cyclinD2 (19%) and the RASSF1A (38%) gene as well as for the microRNA genes mir-9-1 (13%) and mir-9-2 (33%). In contrast to common HCC the APC and CDH1 (E-cadherin) genes were found devoid of any DNA methylation in FLC, whereas the GSTπ1 gene showed comparable DNA methylation in tumor and surrounding tissue at a moderate level. Changes in global DNA methylation level were measured by analyzing methylation status of the highly repetitive LINE-1 sequences. No evidence of global hypomethylation could be found in FLCs, whereas HCCs without cirrhosis showed a significant reduction in global methylation level as described previously.ConclusionsFLCs display frequent and distinct gene-specific hypermethylation in the absence of significant global hypomethylation indicating that these two epigenetic aberrations are induced by different pathways and that full-blown malignancy can develop in the absence of global loss of DNA methylation. Only quantitative DNA methylation detection methodology was able to identify these differences.
Highlights
Inactivation of tumor suppressor genes by aberrant methylation of cytosine residues in the promoter region is an important molecular alteration contributing to the development and progression of malignant tumors [1]
Selection of patients and genes under study Upon review 15 cases of fibrolamellar carcinoma (FLC) were identified from the archives of the Institute of Pathology, Medizinische Hochschule Hannover. 10 cases of common hepatocellular carcinoma (HCC) arising in non-cirrhotic livers were used as a control group (Figure 1)
Common HCC was chosen as a reference because HCC and FLC are regarded as to arise in the same organ and in the very same cell type
Summary
Inactivation of tumor suppressor genes by aberrant methylation of cytosine residues in the promoter region is an important molecular alteration contributing to the development and progression of malignant tumors [1]. It can already be found in pre-malignant lesions and in-situ carcinomas indicating that this epigenetic alteration is an early event in carcinogenesis [2]. We performed epigenetic profiling of a series of FLCs (n = 15) in comparison to common HCC arising in non-cirrhotic livers. Very little is known about epigenetic defects in fibrolamellar carcinoma (FLC), a rare variant of hepatocellular carcinoma that displays distinct clinical and morphological features
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
