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INK4a-ARF alterations in Barrett’s epithelium, intraepithelial neoplasia and Barrett’s adenocarcinoma

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Abstract

Introduction

The INK4a-ARF [CDKN2A]- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16INK4a and p14ARF, which act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway to the carcinogenesis of Barrett’s adenocarcinoma, we analysed the alterations of p14ARFand p16INK4a in preneoplastic and neoplastic lesions of this disease.

Materials and methods

After microdissection, DNA of 15 Barrett’s adenocarcinomas, 40 Barrett’s intraepithelial neoplasms (n=20 low- and n=20 high-grade) and 15 Barrett’s mucosa without neoplasia was analysed for INK4-ARF inactivation using DNA sequence and loss of heterozygosity (LOH) analysis, methylation-specific polymerase chain reaction, restriction-enzyme-related polymerase chain reaction and immunohistochemistry.

Results

We detected 9p21 LOH, p16INK4a methylation and p16INK4a mutations in Barrett’s adenocarcinomas in 5 of 15 (33%), 8 of 15 (53%) and 1 of 15 (7%) patients, respectively. P14ARF was methylated in 3 of 15 (20%) adenocarcinomas. In Barrett’s intraepithelial neoplasia, p16INK4a was altered in 12 of 20 (60%) high-grade and in 4 of 20 (20%) low-grade intraepithelial neoplasms. In Barrett’s mucosa without intraepithelial neoplasia p16INK4a was methylated in one case (7%). P14ARF was intact in Barrett’s mucosa without intraepithelial neoplasia.

Conclusions

We conclude that most Barrett’s intraepithelial neoplasms contain genetic and/or epigenetic INK4a-ARF alterations. Methylation of p16INK4a appears to be the most frequent epigenetic defect in the neoplastic progression of Barrett’s tumourigenesis.

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Authors and Affiliations

  1. Institute of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120 , Magdeburg, Germany

    Michael Vieth, Regine Schneider-Stock & Albert Roessner

  2. Institute of Pathology, University of Leipzig, 04103 , Leipzig, Germany

    Knut Röhrich, Anett Markwarth & Andrea Tannapfel

  3. Clinic of Internal Medicine II, HSK-Clinics Wiesbaden, 65199 , Wiesbaden, Germany

    Andrea May & Christian Ell

  4. Institute of Pathology, Klinikum Bayreuth, 95445 , Bayreuth, Germany

    Manfred Stolte

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  1. Michael Vieth
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Correspondence to Michael Vieth.

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Vieth, M., Schneider-Stock, R., Röhrich, K. et al. INK4a-ARF alterations in Barrett’s epithelium, intraepithelial neoplasia and Barrett’s adenocarcinoma. Virchows Arch 445, 135–141 (2004). https://doi.org/10.1007/s00428-004-1042-0

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  • DOI: https://doi.org/10.1007/s00428-004-1042-0

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