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PLOS ONE  2008 

p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus

DOI: 10.1371/journal.pone.0003809

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Background Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett's esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions The results of this study suggest the environment of the esophagus in BE patients can both generate and select for clones with p16 mutations.


[1]  Sherr CJ, McCormick F (2002) The RB and p53 pathways in cancer. Cancer Cell 2: 103–112.
[2]  Ruas M, Peters G (1998) The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1378: F115–177.
[3]  Pho L, Grossman D, Leachman SA (2006) Melanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma. Curr Opin Oncol 18: 173–179.
[4]  Murphy JA, Barrantes-Reynolds R, Kocherlakota R, Bond JP, Greenblatt MS (2004) The CDKN2A database: Integrating allelic variants with evolution, structure, function, and disease association. Hum Mutat 24: 296–304.
[5]  Rocco JW, Sidransky D (2001) p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp Cell Res 264: 42–55.
[6]  Phillips RW, Wong RK (1991) Barrett's esophagus. Natural history, incidence, etiology, and complications. Gastroenterol Clin North Am 20: 791–816.
[7]  Pohl H, Welch HG (2005) The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 97: 142–146.
[8]  Holmes RS, Vaughan TL (2007) Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol 17: 2–9.
[9]  Brown LM, Devesa SS (2002) Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am 11: 235–256.
[10]  Lin J, Beerm DG (2004) Molecular biology of upper gastrointestinal malignancies. Semin Oncol 31: 476–486.
[11]  Esteve A, Martel-Planche G, Sylla BS, Hollstein M, Hainaut P, et al. (1996) Low frequency of p16/CDKN2 gene mutations in esophageal carcinomas. Int J Cancer 66: 301–304.
[12]  Giroux MA, Audrezet MP, Metges JP, Lozac'h P, Volant A, et al. (2002) Infrequent p16/CDKN2 alterations in squamous cell carcinoma of the oesophagus. Eur J Gastroenterol Hepatol 14: 15–18.
[13]  Gamieldien W, Victor TC, Mugwanya D, Stepien A, Gelderblom WC, et al. (1998) p53 and p16/CDKN2 gene mutations in esophageal tumors from a high-incidence area in South Africa. Int J Cancer 78: 544–549.
[14]  Smeds J, Berggren P, Ma X, Xu Z, Hemminki K, et al. (2002) Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes are major targets for inactivation. Carcinogenesis 23: 645–655.
[15]  Zhou X, Tarmin L, Yin J, Jiang HY, Suzuki H, et al. (1994) The MTS1 gene is frequently mutated in primary human esophageal tumors. Oncogene 9: 3737–3741.
[16]  Reid B, Blount P, Rabinovitch P (2003) Biomarkers in Barrett's Esophagus: A Guideline for Clinicians. Gastrointest Endosc Clin N Am 13: 369–397.
[17]  Reid BJ, Weinstein WM, Lewin KJ, Haggitt RC, VanDeventer G, et al. (1988) Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions. Gastroenterology 94: 81–90.
[18]  Levine DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, et al. (1993) An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett's esophagus [see comments]. Gastroenterology 105: 40–50.
[19]  Reid BJ, Blount PL, Feng Z, Levine DS (2000) Optimizing endoscopic biopsy detection of early cancers in Barrett's high-grade dysplasia. Am J Gastroenterol 95: 3089–3096.
[20]  Blount PL, Galipeau PC, Sanchez CA, Neshat K, Levine DS, et al. (1994) 17p allelic losses in diploid cells of patients with Barrett's esophagus who develop aneuploidy. Cancer Res 54: 2292–2295.
[21]  Paulson TG, Galipeau PC, Reid BJ (1999) Loss of heterozygosity analysis using whole genome amplification, cell sorting, and fluorescence-based PCR. Genome Res 9: 482–491.
[22]  Reid BJ, Sanchez CA, Blount PL, Levine DS (1993) Barrett's esophagus: cell cycle abnormalities in advancing stages of neoplastic progression [see comments]. Gastroenterology 105: 119–129.
[23]  Zhang L, Cui X, Schmitt K, Hubert R, Navidi W, et al. (1992) Whole genome amplification from a single cell: implications for genetic analysis. Proc Natl Acad Sci U S A 89: 5847–5851.
[24]  Wong DJ, Paulson TG, Prevo LJ, Galipeau PC, Longton G, et al. (2001) p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium. Cancer Res 61: 8284–8289.
[25]  Barrett MT, Sanchez CA, Galipeau PC, Neshat K, Emond M, et al. (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.
[26]  Galipeau PC, Cowan DS, Sanchez CA, Barrett MT, Emond MJ, et al. (1996) 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. Proc Natl Acad Sci U S A 93: 7081–7084.
[27]  Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, et al. (2007) NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Med 4: e67.
[28]  Galipeau PC, Prevo LJ, Sanchez CA, Longton GM, Reid BJ (1999) Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue. J Natl Cancer Inst 91: 2087–2095.
[29]  Blount PL, Meltzer SJ, Yin J, Huang Y, Krasna MJ, et al. (1993) Clonal ordering of 17p and 5q allelic losses in Barrett dysplasia and adenocarcinoma. Proc Natl Acad Sci U S A 90: 3221–3225.
[30]  Muzeau F, Flejou JF, Belghiti J, Thomas G, Hamelin R (1997) Infrequent microsatellite instability in oesophageal cancers. Br J Cancer 75: 1336–1339.
[31]  Foulkes WD, Flanders TY, Pollock PM, Hayward NK (1997) The CDKN2A (p16) gene and human cancer. Mol Med 3: 5–20.
[32]  Yarbrough WG, Buckmire RA, Bessho M, Liu ET (1999) Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors. J Natl Cancer Inst 91: 1569–1574.
[33]  Greenblatt MS, Beaudet JG, Gump JR, Godin KS, Trombley L, et al. (2003) Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants. Oncogene 22: 1150–1163.
[34]  Gil J, Peters G (2006) Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7: 667–677.
[35]  Evans MD, Dizdaroglu M, Cooke MS (2004) Oxidative DNA damage and disease: induction, repair and significance. Mutat Res 567: 1–61.
[36]  Prevo LJ, Sanchez CA, Galipeau PC, Reid BJ (1999) p53-mutant clones and field effects in Barrett's esophagus. Cancer Res 59: 4784–4787.
[37]  Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H (2005) Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res 589: 47–65.
[38]  Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3: 276–285.
[39]  Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 313(Pt 1): 17–29.
[40]  Dvorak K, Fass R, Dekel R, Payne CM, Chavarria M, et al. (2006) Esophageal acid exposure at pH
[41]  Wetscher GJ, Hinder RA, Klingler P, Gadenstatter M, Perdikis G, et al. (1997) Reflux esophagitis in humans is a free radical event. Dis Esophagus 10: 29–32. discussion 33.
[42]  Liu L, Ergun G, Ertan A, Woods K, Sachs I, et al. (2003) Detection of oxidative DNA damage in oesophageal biopsies of patients with reflux symptoms and normal pH monitoring. Aliment Pharmacol Ther 18: 693–698.
[43]  Hiroyasu M, Ozeki M, Kohda H, Echizenya M, Tanaka T, et al. (2002) Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis. Am J Pathol 160: 419–424.
[44]  Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S (1999) High incidence of allelic loss on chromosome 5 and inactivation of p15INK4B and p16INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of rats. Oncogene 18: 3793–3797.
[45]  Turker MS, Gage BM, Rose JA, Elroy D, Ponomareva ON, et al. (1999) A novel signature mutation for oxidative damage resembles a mutational pattern found commonly in human cancers. Cancer Res 59: 1837–1839.
[46]  Turner DR, Dreimanis M, Holt D, Firgaira FA, Morley AA (2003) Mitotic recombination is an important mutational event following oxidative damage. Mutat Res 522: 21–26.
[47]  Cameron AJ, Lomboy CT (1992) Barrett's esophagus: age, prevalence, and extent of columnar epithelium. Gastroenterology 103: 1241–1245.
[48]  O'Connor JB, Falk GW, Richter JE (1999) The incidence of adenocarcinoma and dysplasia in Barrett's esophagus: report on the Cleveland Clinic Barrett's Esophagus Registry. Am J Gastroenterol 94: 2037–2042.
[49]  Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68: 820–823.
[50]  Roncalli M, Bosari S, Marchetti A, Buttitta F, Bossi P, et al. (1998) Cell cycle-related gene abnormalities and product expression in esophageal carcinoma. Lab Invest 78: 1049–1057.
[51]  Hardie LJ, Darnton SJ, Wallis YL, Chauhan A, Hainaut P, et al. (2005) p16 expression in Barrett's esophagus and esophageal adenocarcinoma: association with genetic and epigenetic alterations. Cancer Lett 217: 221–230.
[52]  Vieth M, Schneider-Stock R, Rohrich K, May A, Ell C, et al. (2004) INK4a-ARF alterations in Barrett's epithelium, intraepithelial neoplasia and Barrett's adenocarcinoma. Virchows Arch 445: 135–141.
[53]  Gonzalez MV, Artimez ML, Rodrigo L, Lopez-Larrea C, Menendez MJ, et al. (1997) Mutation analysis of the p53, APC, and p16 genes in the Barrett's oesophagus, dysplasia, and adenocarcinoma. J Clin Pathol 50: 212–217.


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