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01-08-2004 | Original Article

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

Authors: Michael Vieth, Regine Schneider-Stock, Knut Röhrich, Andrea May, Christian Ell, Anett Markwarth, Albert Roessner, Manfred Stolte, Andrea Tannapfel

Published in: Virchows Archiv | Issue 2/2004

Abstract

Introduction

The INK4a-ARF [CDKN2A]- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16^INK4a and p14^ARF, 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 p14^ARFand p16^INK4a 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, p16^INK4a methylation and p16^INK4a mutations in Barrett’s adenocarcinomas in 5 of 15 (33%), 8 of 15 (53%) and 1 of 15 (7%) patients, respectively. P14^ARF was methylated in 3 of 15 (20%) adenocarcinomas. In Barrett’s intraepithelial neoplasia, p16^INK4a 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 p16^INK4a was methylated in one case (7%). P14^ARF 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 p16^INK4a appears to be the most frequent epigenetic defect in the neoplastic progression of Barrett’s tumourigenesis.

Ahrendt SA, Eisenberger CF, Yip L, Rashid A, Chow JT, Pitt HA, Sidransky D (1999) Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis-associated cholangiocarcinoma. J Surg Res 84:88–93CrossRefPubMed

Barrett MT, Sanchez CA, Galipeau PC, Neshat K, Emond M, Reid BJ (1996) Allelic loss of 9p21 and mutation of the CDKN2/p16 gene develop as early lesions during neoplastic progression in Barrett’s esophagus. Oncogene 13:1867–1873

Bartsch DK, Sina-Frey M, Lang S, Wild A, Gerdes B, Barth P, Kress R, Grutzmann R, Colombo-Benkmann M, Ziegler A, Hahn SA, Rothmund M, Rieder H (2002) CDKN2A germline mutations in familial pancreatic cancer. Ann Surg 236:730–737CrossRefPubMed

Basu KK, Pick B, Bale R, West KP, de Caestecker JS (2002) Efficacy and one year follow up of argon plasma coagulation therapy for ablation of Barrett’s oesophagus: factors determining persistence and recurrence of Barrett’s epithelium. Gut 51:776–780CrossRefPubMed

Belinsky SA, Snow SS, Nikula KJ, Finch GL, Tellez CS, Palmisano WA (2002) Aberrant CpG island methylation of the p16(INK4a) and estrogen receptor genes in rat lung tumors induced by particulate carcinogens. Carcinogenesis 23:335–339CrossRefPubMed

Bian YS, Osterheld MC, Fontolliet C, Bosman FT, Benhattar J (2002) P16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett’s esophagus. Gastroenterology 122:1113–1121PubMed

Cameron AJ, Ott BJ, Payne WS (1985) The incidence of adenocarcinoma in columnar-lined (Barrett’s) esophagus. N Engl J Med 313:857–859PubMed

Chaubert P, Gayer R, Zimmermann A, Fontolliet C, Stamm B, Bosman F, Shaw P (1997) Germ-line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma. Hepatology 25:1376–1381PubMed

Conio M, Cameron AJ, Romero Y, Branch CD, Schleck CD, Burgart LJ, Zinsmeister AR, Melton LJ 3rd, Locke GR 3rd (2001) Secular trends in the epidemiology and outcome of Barrett’s oesophagus in Olmsted County, Minnesota. Gut 48:304–309CrossRefPubMed

10.

Devesa SS, Blot WJ, Fraumeni JF Jr (1998) Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83:2049–2053

11.

Doak SH, Jenkins GJ, Parry EM, D’Souza FR, Griffiths AP, Toffazal N, Shah V, Baxter JN, Parry JM (2003) Chromosome 4 hyperploidy represents an early aberration in premalignant Barrett’s oesophagus. Gut 52:623–628CrossRefPubMed

12.

Eads CA, Lord RV, Wickramasinghe K, Long TI, Kurumboor SK, Bernstein L, Peters JH, DeMeester SR, DeMeester TR, Skinner KA, Laird PW (2001) Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res 61:3410–3418PubMed

13.

Egger K, Werner M, Meining A, Ott R, Allescher HD, Höfler H, Classen M, Rösch T (2003) Biopsy surveillance is still necessary in patients with Barrett’s oesophagus despite new endoscopic imaging techniques. Gut 52:18–23CrossRefPubMed

14.

Faller G, Borchard F, Ell C, Seitz G, Stolte M, Walch A, Rüschoff J, Working Group for Gastroenterological Pathology of the German Society for Pathology (2003) Histopathological diagnosis of Barrett’s mucosa and associated neoplasias: results of a consensus conference of the Working Group for Gastroenterological Pathology of the German Society for Pathology on 22 September 2001 in Erlangen. Virchows Arch 443:597–601CrossRefPubMed

15.

Fitzgerald RC (2003) Ablative mucosectomy is the procedure of choice to prevent Barrett’s cancer. Gut 52:16–17CrossRefPubMed

16.

Fitzgerald RC, Abdalla S, Onwuegbusi BA, Sirieix P, Saeed IT, Burnham WR, Farthing MJ (2002) Inflammatory gradient in Barrett’s oesophagus: implications for disease complications. Gut 51:316–322CrossRefPubMed

17.

Fujii T, Nakagawa S, Hanzawa M, Sueyoshi S, Fujita H, Shirouzu K, Yamana H (2003) Immunohistological study of cell-cycle-related factors, oncogene expression, and cell proliferation in adenocarcinoma development in Barrett’s esophagus. Oncol Rep 10:427–431PubMed

18.

Haggitt RC (1994) Barrett’s esophagus, dysplasia, and adenocarcinoma. Hum Pathol 25:982–993PubMed

19.

Hamilton SR, Aaltonen LA (eds) (2000) WHO Pathology and genetics. IARC Press, Lyon, pp 173–200

20.

Hearle N, Damato BE, Humphreys J, Wixey J, Green H, Stone J, Easton DF, Houlston RS (2003) Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma. Invest Ophthalmol Vis Sci 44:458–462CrossRefPubMed

21.

Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC (1994) Germline p16 mutations in familial melanoma. Nat Genet 8:15–21PubMed

22.

Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA (2001) Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61:3573–3577PubMed

23.

Jang TJ, Kim DI, Shin YM, Chang HK, Yang CH (2001) p16(INK4a) Promoter hypermethylation of non-tumorous tissue adjacent to gastric cancer is correlated with glandular atrophy and chronic inflammation. Int J Cancer 93:629–634CrossRefPubMed

24.

Jen J, Harper JW, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW, Vogelstein B (1994) Deletion of p16 and p15 genes in brain tumors. Cancer Res 54:6353–6358PubMed

25.

Karayan L, Riou JF, Seite P, Migeon J, Cantereau A, Larsen CJ (2001) Human ARF protein interacts with topoisomerase I and stimulates its activity. Oncogene 20:836–848PubMed

26.

Klump B, Hsieh CJ, Nehls O, Dette S, Holzmann K, Kiesslich R, Jung M, Sinn U, Ortner M, Porschen R, Gregor M (1998) Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett’s esophagus. Gastroenterology 115:1381–1386PubMed

27.

Lo DYM, Wong IHN, Zhang J, Tein MS, Ng MH, Hjelm NM (1999) Quantitative analysis of aberrant p16 methylation using real-time quantitative methylation-specific polymerase chain reaction. Cancer Res 59:3899–3903PubMed

28.

Martin A, Baran-Marzak F, El Mansouri S, Legendre C, Leblond V, Charlotte F, Davi F, Canioni D, Raphael M (2000) Expression of p16/INK4a in posttransplantation lymphoproliferative disorders. Am J Pathol 156:1573–1579PubMed

29.

May A, Gossner L, Pech O, Fritz A, Günter E, Mayer G, Müller H, Seitz G, Vieth M, Stolte M, Ell C (2002) Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus: acute-phase and intermediate results of a new treatment approach. Eur J Gastroenterol Hepatol 14:1085–1091CrossRefPubMed

30.

Montgomery E, Bronner MP, Goldblum J, Greenson JK, Haber MM, Hart J, Lamps LW, Lauwers GY, Lazenby AJ, Lewin DN, Robert ME, Toledano AY, Shyr Y, Washington K (2001) Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol 32:368–378CrossRefPubMed

31.

Morales CP, Souza RF, Spechler SJ (2002) Hallmarks of cancer progression in Barrett’s oesophagus. Lancet 360:1587–1589CrossRefPubMed

32.

Ormsby AH, Petras RE, Henricks WH, Rice TW, Rybicki LA, Richter JE, Goldblum JR (2002) Observer variation in the diagnosis of superficial oesophageal adenocarcinoma. Gut 51:671–676CrossRefPubMed

33.

Ortner MA, Ebert B, Hein E, Zumbusch K, Nolte D, Sukowski U, Weber-Eibel J, Fleige B, Dietel M, Stolte M, Oberhuber G, Porschen R, Klump B, Hortnagl H, Lochs H, Rinneberg H (2003) Time gated fluorescence spectroscopy in Barrett’s oesophagus. Gut 52:28–33CrossRefPubMed

34.

Pera M (2000) Epidemiology of esophageal cancer, especially adenocarcinoma of the esophagus and esophagogastric junction. Recent Results Cancer Res 155:1–14PubMed

35.

Rashid A, Shen L, Morris JS, Issa JP, Hamilton SR (2001) CpG island methylation in colorectal adenomas. Am J Pathol 159:1129–1135PubMed

36.

Reid BJ (1991) Barrett’s esophagus and esophageal adenocarcinoma. Gastroenterol Clin North Am 20:817–834PubMed

37.

Rutter JL, Goldstein AM, Dávila MR, Tucker MA, Struewing JP (2003) CDKN2A point mutations D153spl(c.457G>T) and IVS2+1G>T result in aberrant splice products affecting both p16INK4a and p14ARF. Oncogene 44:4444–4448CrossRef

38.

Sharma P, Weston AP, Topalovski M, Cherian R, Bhattacharyya A, Sampliner RE (2003) Magnification chromoendoscopy for the detection of intestinal metaplasia and dysplasia in Barrett’s oesophagus. Gut 52:24–27CrossRefPubMed

39.

Sherr CJ (2001) The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol 2:731–737CrossRefPubMed

40.

Spechler SJ (1994) Barrett’s esophagus. Semin Oncol 21:431–437PubMed

41.

Spechler SJ (2002) Barrett’s esophagus. N Engl J Med 346:836–842CrossRefPubMed

42.

Tannapfel A, Benicke M, Katalinic A, Uhlmann D, Köckerling F, Hauss J, Wittekind C (2000) Frequency of p16INK4A alterations and k-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut 47:721–727CrossRefPubMed

43.

Tannapfel A, Busse C, Geißler F, Witzigmann H, Hauss J, Wittekind C (2002) INK4a-ARF alterations in liver cell adenoma. Gut 51:253–258CrossRefPubMed

44.

Tselepis C, Morris CD, Wakelin D, Hardy R, Perry I, Luong QT, Harper E, Harrison R, Attwood SE, Jankowski JA (2003) Upregulation of oncogene c-myc in Barrett’s adenocarcinoma: induction of c-myc by acidified bile acid in vitro. Gut 52:174–180CrossRefPubMed

45.

Wheeler JM, Bodmer WF, Mortensen NJ (2000) DNA mismatch repair genes and colorectal cancer. Gut 47:148–153CrossRefPubMed

46.

Wong DJ, Paulson TG, Prevo LJ, Galipeau C, Longton G, Blount PL, Reid BJ (2001) P16^INK4a lesions are common, early abnormalities that undergo clonal expansion in Barrett’s metaplastic epithelium. Cancer Res 61:8284–8289PubMed

Title: INK4a-ARF alterations in Barrett’s epithelium, intraepithelial neoplasia and Barrett’s adenocarcinoma
Authors: Michael Vieth
Regine Schneider-Stock
Knut Röhrich
Andrea May
Christian Ell
Anett Markwarth
Albert Roessner
Manfred Stolte
Andrea Tannapfel
Publication date: 01-08-2004
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 2/2004
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-004-1042-0

At a glance: The STEP trials

Springer Medicine

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

Abstract

Introduction

Materials and methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Materials and methods

Results

Conclusions

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