INK4a-ARF alterations in liver cell adenoma

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Abstract
Background: The INK4a-ARF (CDKN2A) locus on chromosome 9p21 encodes two tumour suppressor proteins, p16INK4a and p14ARF, whose functions are inactivated in many human cancers. Aims: To evaluate p14ARF and p16INK4a 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 p14ARF and p16INK4a were assessed by differential PCR. Results: Methylation of p14ARF was found in 3/25 cases (12%) and alterations in p16INK4a 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. p16INK4a methylation appeared in the context of an unmethylated p14ARF promoter in six cases. In normal liver tissue, p14ARF or p16INK4a alterations were not observed. Conclusions: Our data suggest that p14ARF methylation occurs independently of p16INK4a alterations in liver cell adenomas. Furthermore, methylation of p14ARF and p16INK4a may be a result of cell cycle deregulation and does not seem to be a prerequisite of malignancy.