Deregulation of RB1 expression by loss of imprinting in human hepatocellular carcinoma. Issue 4 (16th June 2014)

• Record Type: Journal Article
• Authors: Anwar, Sumadi Lukman; Krech, Till; Hasemeier, Britta; Schipper, Elisa; Schweitzer, Nora; Vogel, Arndt; Kreipe, Hans; Lehmann, Ulrich
• Is Part Of: Journal of pathology. Volume 233:Issue 4(2014)
• Page Start: 392
• Page End: 401
• Publication Date: 2014-06-16
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4376
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4376-abs-0001"> <title>Abstract</title> <p id="path4376-para-0001">The tumour suppressor gene <italic>RB</italic>1 is frequently silenced in many different types of human cancer, including hepatocellular carcinoma (HCC). However, mutations of the <italic>RB1</italic> gene are relatively rare in HCC. A systematic screen for the identification of imprinted genes deregulated in human HCC revealed that <italic>RB1</italic> shows imprint abnormalities in a high proportion of primary patient samples. Altogether, 40% of the HCC specimens (16/40) showed hyper‐ or hypomethylation at the CpG island in intron 2 of the <italic>RB1</italic> gene. Re‐analysis of publicly available genome‐wide DNA methylation data confirmed these findings in two independent HCC cohorts. Loss of correct DNA methylation patterns at the <italic>RB1</italic> locus leads to the aberrant expression of an alternative <italic>RB1–E2B</italic> transcript, as measured by quantitative real‐time PCR. Demethylation at the intron 2 CpG island by <italic>DNMT1</italic> knock‐down or aza‐deoxycytidine (DAC) treatment stimulated expression of the <italic>RB1–E2B</italic> transcript, accompanied by diminished <italic>RB1</italic> main transcript expression. No aberrant DNA methylation was found at the <italic>RB1</italic> locus in hepatocellular adenoma (HCA, <italic>n =</italic> 10), focal nodular hyperplasia (FNH, <italic>n =</italic> 5) and their corresponding adjacent liver tissue specimens. Deregulated <italic>RB1</italic> expression due to hyper‐ or hypomethylation in intron 2 of the <italic>RB1</italic> gene is found in tumours without loss of heterozygosity and is associated with a decrease in overall survival (<italic>p =</italic> 0.032) if caused by hypermethylation of CpG85. This unequivocally demonstrates that loss of imprinting represents an important additional mechanism for <italic>RB1</italic> pathway inactivation in human HCC, complementing well‐described molecular defects. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</p> </abstract>