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INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas.
Oncogene. 2001 Oct 25; 20(48):7104-9.O

Abstract

The INK4a-ARF (CDKN2A)- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16(INK4a) and p14(ARF), that act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in tumorigenesis of hepatocellular carcinoma (HCC), we analysed the alterations of p14(ARF), p16(INC4a) and p53. After microdissection, DNA of 71 hepatocellular carcinomas was analysed for INK4-ARF inactivation and p53 mutation by DNA sequence analysis, methylation-specific PCR (MSP), restriction-enzyme related polymerase chain reaction (RE-PCR), mRNA expression and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INC4a) were assessed by differential PCR. Inactivation of p14(ARF) was found in 11/71 cases (15%), alterations of p16(INK4a) occurred in 47/71 carcinomas (66%), which correlated with loss of mRNA transcription. Five tumours (7%) had homozygous deletions of the INK4a-ARF locus. We failed to detect specific mutations of both exons. P16(INK4a) methylation with an unmethylated p14(ARF) promotor appeared in 39 cases. Mutations of p53 were found in 30 of 71 HCC (42%), and only one of them harboured p14(ARF) inactivation. We failed to establish alterations of the INK4a-ARF locus or p53 status as independent prognostic factor in these tumours. Our data indicate, that p14(ARF) methylation occurs independently of p16(INK4a) alterations in a subset of HCC together with wild type p53. The INK4a-ARF-/p53-pathway was disrupted in 86% of HCC, either by p53 mutations or by INK4a-ARF inactivation, and may have co-operative effects in hepatocarcinogenesis.

Authors+Show Affiliations

Institute of Pathology, University of Leipzig, Liebigstr. 26, 04103 Leipzig, Germany. tana@medizin.uni-leipzig.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11704835

Citation

Tannapfel, A, et al. "INK4a-ARF Alterations and P53 Mutations in Hepatocellular Carcinomas." Oncogene, vol. 20, no. 48, 2001, pp. 7104-9.
Tannapfel A, Busse C, Weinans L, et al. INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene. 2001;20(48):7104-9.
Tannapfel, A., Busse, C., Weinans, L., Benicke, M., Katalinic, A., Geissler, F., Hauss, J., & Wittekind, C. (2001). INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene, 20(48), 7104-9.
Tannapfel A, et al. INK4a-ARF Alterations and P53 Mutations in Hepatocellular Carcinomas. Oncogene. 2001 Oct 25;20(48):7104-9. PubMed PMID: 11704835.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. AU - Tannapfel,A, AU - Busse,C, AU - Weinans,L, AU - Benicke,M, AU - Katalinic,A, AU - Geissler,F, AU - Hauss,J, AU - Wittekind,C, PY - 2001/05/22/received PY - 2001/07/18/revised PY - 2001/08/07/accepted PY - 2001/11/13/pubmed PY - 2002/1/5/medline PY - 2001/11/13/entrez SP - 7104 EP - 9 JF - Oncogene JO - Oncogene VL - 20 IS - 48 N2 - The INK4a-ARF (CDKN2A)- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16(INK4a) and p14(ARF), that act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in tumorigenesis of hepatocellular carcinoma (HCC), we analysed the alterations of p14(ARF), p16(INC4a) and p53. After microdissection, DNA of 71 hepatocellular carcinomas was analysed for INK4-ARF inactivation and p53 mutation by DNA sequence analysis, methylation-specific PCR (MSP), restriction-enzyme related polymerase chain reaction (RE-PCR), mRNA expression and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INC4a) were assessed by differential PCR. Inactivation of p14(ARF) was found in 11/71 cases (15%), alterations of p16(INK4a) occurred in 47/71 carcinomas (66%), which correlated with loss of mRNA transcription. Five tumours (7%) had homozygous deletions of the INK4a-ARF locus. We failed to detect specific mutations of both exons. P16(INK4a) methylation with an unmethylated p14(ARF) promotor appeared in 39 cases. Mutations of p53 were found in 30 of 71 HCC (42%), and only one of them harboured p14(ARF) inactivation. We failed to establish alterations of the INK4a-ARF locus or p53 status as independent prognostic factor in these tumours. Our data indicate, that p14(ARF) methylation occurs independently of p16(INK4a) alterations in a subset of HCC together with wild type p53. The INK4a-ARF-/p53-pathway was disrupted in 86% of HCC, either by p53 mutations or by INK4a-ARF inactivation, and may have co-operative effects in hepatocarcinogenesis. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/11704835/INK4a_ARF_alterations_and_p53_mutations_in_hepatocellular_carcinomas_ L2 - http://dx.doi.org/10.1038/sj.onc.1204902 DB - PRIME DP - Unbound Medicine ER -