LIVER DISEASE

INK4a-ARF alterations in liver cell adenoma

A Tannapfel¹, C Busse¹, F Geißler², H Witzigmann², J Hauss² and C Wittekind¹

¹ Institute of Pathology, University of Leipzig, Liebigstr 26, 04103 Leipzig, Germany
² Department of Abdominal, Vascular, and Transplantation Surgery II, University of Leipzig, Liebigstr 20a, 04103 Leipzig, Germany

Correspondence to:
Correspondence to:
Dr A Tannapfel, Institute of Pathology, University of Leipzig, Liebigstraße 26, 04103 Leipzig, Germany;
tana{at}medizin.uni-leipzig.de

Background: The INK4a-ARF (CDKN2A) locus on chromosome 9p21 encodes two tumour suppressor proteins, p16^INK4a and p14^ARF, whose functions are inactivated in many human cancers.

Aims: To evaluate p14^ARF and p16^INK4a alterations in liver cell adenoma.

Methods: After microdissection, DNA from 25 liver cell adenomas and corresponding normal liver tissue were analysed for INK4-ARF inactivation by DNA sequence analysis, methylation specific polymerase chain reaction, restriction enzyme related-polymerase chain reaction (RE-PCR), mRNA expression, microsatellite analysis, and immunohistochemistry. In addition, microdeletion of p14^ARF and p16^INK4a were assessed by differential PCR.

Results: Methylation of p14^ARF was found in 3/25 cases (12%) and alterations in p16^INK4a occurred in 6/25 liver cell adenomas (24%) which correlated with loss of mRNA transcription. We failed to detect microdeletions or specific mutations of both exons. p16^INK4a methylation appeared in the context of an unmethylated p14^ARF promoter in six cases. In normal liver tissue, p14^ARF or p16^INK4a alterations were not observed.

Conclusions: Our data suggest that p14^ARF methylation occurs independently of p16^INK4a alterations in liver cell adenomas. Furthermore, methylation of p14^ARF and p16^INK4a may be a result of cell cycle deregulation and does not seem to be a prerequisite of malignancy.

Keywords: liver cell adenoma; p14^ARF; p16^INK4a; methylation; cell cycle deregulation

Abbreviations: LCA, liver cell adenoma; MSP, methylation specific polymerase chain reaction; RE-PCR, restriction enzyme-related polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; SSCP, single strand conformational polymorphism

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