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. 1998 Apr;51(2):71–79. doi: 10.1136/mp.51.2.71

p53 alterations in oesophageal cancer: association with clinicopathological features, risk factors, and survival.

A G Casson 1, M Tammemagi 1, S Eskandarian 1, M Redston 1, J McLaughlin 1, H Ozcelik 1
PMCID: PMC395613  PMID: 9713589

Abstract

AIM: To characterise the spectrum of p53 alterations (gene mutations and protein accumulation) in a consecutive series of surgically resected oesophageal cancers, and to evaluate associations with clinicopathological findings (age, sex, tumour histology, grade, and stage), potential risk factors (alcohol, tobacco, hot beverage consumption, history of gastrooesophageal reflux disease and antacid use), and survival. METHODS: The case series comprised 61 sequentially accrued patients with primary oesophageal carcinomas. Genomic DNA was extracted from banked (frozen) tumours and matched normal mucosal tissue; p53 mutations (exons 4-10) were studied by means of polymerase chain reaction (PCR)/single strand conformation polymorphism (SSCP) analysis and DNA sequencing. Immunohistochemistry (DO7, CM1) was used to assess cell nuclear p53 protein accumulation. Risk factor data, overall and disease free survival were measured prospectively, and analysis was carried out at the univariate level using Kaplan-Meier survival curves with log rank tests, and in multivariate analysis using Cox's proportional hazards models (parsimonious and fully adjusted). RESULTS: p53 mutations were found in 59% (36 of 61) and p53 protein accumulation was detected in 39% (24 of 61) of oesophageal cancers. Eighty eight per cent (23 of 26) of poorly differentiated tumours had p53 alterations compared with 57% (20 of 35) of moderate/well differentiated tumours (odds ratio (OR) = 5.575; p = 0.013). p53 mutations increased significantly with increasing consumption of hot beverages (measured by the average temperature of beverage, number consumed daily, and an index made by multiplying the two variables together) using both univariate (OR = 18.6; p = 0.0025) and multivariate (OR = 24.5; p = 0.0025) analysis. p53 alterations were associated with reduced disease free and overall survival (p = 0.051, log rank), with a univariate (unadjusted) hazard ratio (HR) of 2.241 (95% confidence limits (CL) = 0.973, 5.159; p = 0.058) for overall survival. By multivariate analysis adjusted for other relevant variables, the HR for tumours with p53 alterations was estimated at 2.913 (95% CL = 1.069, 7.936; p = 0.036) for overall survival. CONCLUSIONS: This study reports novel p53 mutations (exon 10), and an association between increasing consumption of hot beverages as a risk factor for p53 mediated oesophageal cancer. p53 is a potentially useful prognostic marker in this disease.

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Selected References

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  1. Allred D. C., Clark G. M., Elledge R., Fuqua S. A., Brown R. W., Chamness G. C., Osborne C. K., McGuire W. L. Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst. 1993 Feb 3;85(3):200–206. doi: 10.1093/jnci/85.3.200. [DOI] [PubMed] [Google Scholar]
  2. Bennett W. P., Hollstein M. C., He A., Zhu S. M., Resau J. H., Trump B. F., Metcalf R. A., Welsh J. A., Midgley C., Lane D. P. Archival analysis of p53 genetic and protein alterations in Chinese esophageal cancer. Oncogene. 1991 Oct;6(10):1779–1784. [PubMed] [Google Scholar]
  3. Bennett W. P., Hollstein M. C., Metcalf R. A., Welsh J. A., He A., Zhu S. M., Kusters I., Resau J. H., Trump B. F., Lane D. P. p53 mutation and protein accumulation during multistage human esophageal carcinogenesis. Cancer Res. 1992 Nov 1;52(21):6092–6097. [PubMed] [Google Scholar]
  4. Blount P. L., Galipeau P. C., Sanchez C. A., Neshat K., Levine D. S., Yin J., Suzuki H., Abraham J. M., Meltzer S. J., Reid B. J. 17p allelic losses in diploid cells of patients with Barrett's esophagus who develop aneuploidy. Cancer Res. 1994 May 1;54(9):2292–2295. [PubMed] [Google Scholar]
  5. Campomenosi P., Conio M., Bogliolo M., Urbini S., Assereto P., Aprile A., Monti P., Aste H., Lapertosa G., Inga A. p53 is frequently mutated in Barrett's metaplasia of the intestinal type. Cancer Epidemiol Biomarkers Prev. 1996 Jul;5(7):559–565. [PubMed] [Google Scholar]
  6. Casson A. G., Kerkvliet N., O'Malley F. Prognostic value of p53 protein in esophageal adenocarcinoma. J Surg Oncol. 1995 Sep;60(1):5–11. doi: 10.1002/jso.2930600103. [DOI] [PubMed] [Google Scholar]
  7. Casson A. G., Mukhopadhyay T., Cleary K. R., Ro J. Y., Levin B., Roth J. A. p53 gene mutations in Barrett's epithelium and esophageal cancer. Cancer Res. 1991 Aug 15;51(16):4495–4499. [PubMed] [Google Scholar]
  8. Coggi G., Bosari S., Roncalli M., Graziani D., Bossi P., Viale G., Buffa R., Ferrero S., Piazza M., Blandamura S. p53 protein accumulation and p53 gene mutation in esophageal carcinoma. A molecular and immunohistochemical study with clinicopathologic correlations. Cancer. 1997 Feb 1;79(3):425–432. doi: 10.1002/(sici)1097-0142(19970201)79:3<425::aid-cncr1>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  9. Dalquen P., Sauter G., Torhorst J., Schultheiss E., Jordan P., Lehmann S., Solèr M., Stulz P., Mihatsch M. J., Gudat F. Nuclear p53 overexpression is an independent prognostic parameter in node-negative non-small cell lung carcinoma. J Pathol. 1996 Jan;178(1):53–58. doi: 10.1002/(SICI)1096-9896(199601)178:1<53::AID-PATH415>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  10. Devesa S. S., Blot W. J., Stone B. J., Miller B. A., Tarone R. E., Fraumeni J. F., Jr Recent cancer trends in the United States. J Natl Cancer Inst. 1995 Feb 1;87(3):175–182. doi: 10.1093/jnci/87.3.175. [DOI] [PubMed] [Google Scholar]
  11. Elledge R. M. Assessing p53 status in breast cancer prognosis: where should you put the thermometer if you think your p53 is sick? J Natl Cancer Inst. 1996 Feb 21;88(3-4):141–143. doi: 10.1093/jnci/88.3-4.141. [DOI] [PubMed] [Google Scholar]
  12. Farrow D. C., Vaughan T. L. Determinants of survival following the diagnosis of esophageal adenocarcinoma (United States). Cancer Causes Control. 1996 May;7(3):322–327. doi: 10.1007/BF00052937. [DOI] [PubMed] [Google Scholar]
  13. Fléjou J. F., Potet F., Muzeau F., Le Pelletier F., Fékété F., Hénin D. Overexpression of p53 protein in Barrett's syndrome with malignant transformation. J Clin Pathol. 1993 Apr;46(4):330–333. doi: 10.1136/jcp.46.4.330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Furihata M., Ohtsuki Y., Ogoshi S., Takahashi A., Tamiya T., Ogata T. Prognostic significance of human papillomavirus genomes (type-16, -18) and aberrant expression of p53 protein in human esophageal cancer. Int J Cancer. 1993 May 8;54(2):226–230. doi: 10.1002/ijc.2910540211. [DOI] [PubMed] [Google Scholar]
  15. Galiana C., Lozano J. C., Bancel B., Nakazawa H., Yamasaki H. High frequency of Ki-ras amplification and p53 gene mutations in adenocarcinomas of the human esophagus. Mol Carcinog. 1995 Dec;14(4):286–293. doi: 10.1002/mc.2940140409. [DOI] [PubMed] [Google Scholar]
  16. Gao H., Wang L. D., Zhou Q., Hong J. Y., Huang T. Y., Yang C. S. p53 tumor suppressor gene mutation in early esophageal precancerous lesions and carcinoma among high-risk populations in Henan, China. Cancer Res. 1994 Aug 15;54(16):4342–4346. [PubMed] [Google Scholar]
  17. Gleeson C. M., Sloan J. M., McGuigan J. A., Ritchie A. J., Russell S. E. Base transitions at CpG dinucleotides in the p53 gene are common in esophageal adenocarcinoma. Cancer Res. 1995 Aug 1;55(15):3406–3411. [PubMed] [Google Scholar]
  18. Goukon Y., Sasano H., Nishihira T., Nagura H., Mori S. p53 overexpression in human esophageal carcinoma: a correlation with tumor DNA ploidy and two parameter flow cytometric study. Anticancer Res. 1994 May-Jun;14(3B):1305–1312. [PubMed] [Google Scholar]
  19. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  20. Hamelin R., Fléjou J. F., Muzeau F., Potet F., Laurent-Puig P., Fékété F., Thomas G. TP53 gene mutations and p53 protein immunoreactivity in malignant and premalignant Barrett's esophagus. Gastroenterology. 1994 Oct;107(4):1012–1018. doi: 10.1016/0016-5085(94)90225-9. [DOI] [PubMed] [Google Scholar]
  21. Harris C. C., Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med. 1993 Oct 28;329(18):1318–1327. doi: 10.1056/NEJM199310283291807. [DOI] [PubMed] [Google Scholar]
  22. Hollstein M. C., Metcalf R. A., Welsh J. A., Montesano R., Harris C. C. Frequent mutation of the p53 gene in human esophageal cancer. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9958–9961. doi: 10.1073/pnas.87.24.9958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hollstein M., Shomer B., Greenblatt M., Soussi T., Hovig E., Montesano R., Harris C. C. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res. 1996 Jan 1;24(1):141–146. doi: 10.1093/nar/24.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Huang Y., Meltzer S. J., Yin J., Tong Y., Chang E. H., Srivastava S., McDaniel T., Boynton R. F., Zou Z. Q. Altered messenger RNA and unique mutational profiles of p53 and Rb in human esophageal carcinomas. Cancer Res. 1993 Apr 15;53(8):1889–1894. [PubMed] [Google Scholar]
  25. Jankowski J., Coghill G., Hopwood D., Wormsley K. G. Oncogenes and onco-suppressor gene in adenocarcinoma of the oesophagus. Gut. 1992 Aug;33(8):1033–1038. doi: 10.1136/gut.33.8.1033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Launoy G., Milan C., Day N. E., Faivre J., Pienkowski P., Gignoux M. Oesophageal cancer in France: potential importance of hot alcoholic drinks. Int J Cancer. 1997 Jun 11;71(6):917–923. doi: 10.1002/(sici)1097-0215(19970611)71:6<917::aid-ijc1>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  27. Liang Y. Y., Estève A., Martel-Planche G., Takahashi S., Lu S. H., Montesano R., Hollstein M. p53 mutations in esophageal tumors from high-incidence areas of China. Int J Cancer. 1995 May 29;61(5):611–614. doi: 10.1002/ijc.2910610505. [DOI] [PubMed] [Google Scholar]
  28. McGuire W. L. Breast cancer prognostic factors: evaluation guidelines. J Natl Cancer Inst. 1991 Feb 6;83(3):154–155. doi: 10.1093/jnci/83.3.154. [DOI] [PubMed] [Google Scholar]
  29. Meltzer S. J., Yin J., Huang Y., McDaniel T. K., Newkirk C., Iseri O., Vogelstein B., Resau J. H. Reduction to homozygosity involving p53 in esophageal cancers demonstrated by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4976–4980. doi: 10.1073/pnas.88.11.4976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Montesano R., Hollstein M., Hainaut P. Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review. Int J Cancer. 1996 Jun 21;69(3):225–235. doi: 10.1002/(SICI)1097-0215(19960621)69:3<225::AID-IJC13>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
  31. Moskaluk C. A., Heitmiller R., Zahurak M., Schwab D., Sidransky D., Hamilton S. R. p53 and p21(WAF1/CIP1/SDI1) gene products in Barrett esophagus and adenocarcinoma of the esophagus and esophagogastric junction. Hum Pathol. 1996 Nov;27(11):1211–1220. doi: 10.1016/s0046-8177(96)90317-2. [DOI] [PubMed] [Google Scholar]
  32. Muñoz N., Victora C. G., Crespi M., Saul C., Braga N. M., Correa P. Hot maté drinking and precancerous lesions of the oesophagus: an endoscopic survey in southern Brazil. Int J Cancer. 1987 Jun 15;39(6):708–709. doi: 10.1002/ijc.2910390609. [DOI] [PubMed] [Google Scholar]
  33. Neshat K., Sanchez C. A., Galipeau P. C., Blount P. L., Levine D. S., Joslyn G., Reid B. J. p53 mutations in Barrett's adenocarcinoma and high-grade dysplasia. Gastroenterology. 1994 Jun;106(6):1589–1595. doi: 10.1016/0016-5085(94)90415-4. [DOI] [PubMed] [Google Scholar]
  34. Ozçelik H., Andrulis I. L. Multiplex PCR-SSCP for simultaneous screening for mutations in several exons of p53. Biotechniques. 1995 May;18(5):742–744. [PubMed] [Google Scholar]
  35. Ozçelik H., Mousses S., Andrulis I. L. Low levels of expression of an inhibitor of cyclin-dependent kinases (CIP1/WAF1) in primary breast carcinomas with p53 mutations. Clin Cancer Res. 1995 Aug;1(8):907–912. [PubMed] [Google Scholar]
  36. Rolón P. A., Castellsagué X., Benz M., Muñoz N. Hot and cold mate drinking and esophageal cancer in Paraguay. Cancer Epidemiol Biomarkers Prev. 1995 Sep;4(6):595–605. [PubMed] [Google Scholar]
  37. Sarbia M., Porschen R., Borchard F., Horstmann O., Willers R., Gabbert H. E. p53 protein expression and prognosis in squamous cell carcinoma of the esophagus. Cancer. 1994 Oct 15;74(8):2218–2223. doi: 10.1002/1097-0142(19941015)74:8<2218::aid-cncr2820740803>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  38. Sasano H., Miyazaki S., Gooukon Y., Nishihira T., Sawai T., Nagura H. Expression of p53 in human esophageal carcinoma: an immunohistochemical study with correlation to proliferating cell nuclear antigen expression. Hum Pathol. 1992 Nov;23(11):1238–1243. doi: 10.1016/0046-8177(92)90291-a. [DOI] [PubMed] [Google Scholar]
  39. Sauter E. R., Keller S. M., Erner S. M. p53 correlates with improved survival in patients with esophageal adenocarcinoma. J Surg Oncol. 1995 Apr;58(4):269–273. doi: 10.1002/jso.2930580414. [DOI] [PubMed] [Google Scholar]
  40. Shimaya K., Shiozaki H., Inoue M., Tahara H., Monden T., Shimano T., Mori T. Significance of p53 expression as a prognostic factor in oesophageal squamous cell carcinoma. Virchows Arch A Pathol Anat Histopathol. 1993;422(4):271–276. doi: 10.1007/BF01608335. [DOI] [PubMed] [Google Scholar]
  41. Shin D. M., Lee J. S., Lippman S. M., Lee J. J., Tu Z. N., Choi G., Heyne K., Shin H. J., Ro J. Y., Goepfert H. p53 expressions: predicting recurrence and second primary tumors in head and neck squamous cell carcinoma. J Natl Cancer Inst. 1996 Apr 17;88(8):519–529. doi: 10.1093/jnci/88.8.519. [DOI] [PubMed] [Google Scholar]
  42. Sorsdahl K., Casson A. G., Troster M., Van Meyel D., Inculet R., Chambers A. F. p53 and ras gene expression in human esophageal cancer and Barrett's epithelium: a prospective study. Cancer Detect Prev. 1994;18(3):179–185. [PubMed] [Google Scholar]
  43. Vijeyasingam R., Darnton S. J., Jenner K., Allen C. A., Billingham C., Matthews H. R. Expression of p53 protein in oesophageal carcinoma: clinicopathological correlation and prognostic significance. Br J Surg. 1994 Nov;81(11):1623–1626. doi: 10.1002/bjs.1800811120. [DOI] [PubMed] [Google Scholar]
  44. Volant A., Nousbaum J. B., Giroux M. A., Roué-Quintin I., Metges J. P., Férec C., Gouérou H., Robaszkiewicz M. p53 protein accumulation in oesophageal squamous cell carcinomas and precancerous lesions. J Clin Pathol. 1995 Jun;48(6):531–534. doi: 10.1136/jcp.48.6.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wagata T., Shibagaki I., Imamura M., Shimada Y., Toguchida J., Yandell D. W., Ikenaga M., Tobe T., Ishizaki K. Loss of 17p, mutation of the p53 gene, and overexpression of p53 protein in esophageal squamous cell carcinomas. Cancer Res. 1993 Feb 15;53(4):846–850. [PubMed] [Google Scholar]
  46. Wang L. D., Hong J. Y., Qiu S. L., Gao H., Yang C. S. Accumulation of p53 protein in human esophageal precancerous lesions: a possible early biomarker for carcinogenesis. Cancer Res. 1993 Apr 15;53(8):1783–1787. [PubMed] [Google Scholar]
  47. Younes M., Lebovitz R. M., Lechago L. V., Lechago J. p53 protein accumulation in Barrett's metaplasia, dysplasia, and carcinoma: a follow-up study. Gastroenterology. 1993 Dec;105(6):1637–1642. doi: 10.1016/0016-5085(93)91058-p. [DOI] [PubMed] [Google Scholar]

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