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The American Journal of Pathology logoLink to The American Journal of Pathology
. 1993 Apr;142(4):1163–1172.

Neoplasia of the ampulla of Vater. Ki-ras and p53 mutations.

A Scarpa 1, P Capelli 1, G Zamboni 1, T Oda 1, K Mukai 1, F Bonetti 1, G Martignoni 1, C Iacono 1, G Serio 1, S Hirohashi 1
PMCID: PMC1886879  PMID: 8475992

Abstract

Eleven tumors of the ampulla of Vater (5 stage IV and 2 stage II adenocarcinomas, 1 stage II papillary carcinoma, 1 neuroendocrine carcinoma, and 2 adenomas, one with foci of carcinoma) were examined for Ki-ras and p53 gene mutations by single-strand conformation polymorphism analysis and direct sequencing of polymerase chain reaction-amplified DNA fragments. Ki-ras mutations were found in one adenocarcinoma and in the adenoma with foci of carcinoma, both involving mainly the intraduodenal bile duct component of the ampulla. Seven cases showed p53 gene mutations: four advanced-stage adenocarcinomas, the papillary carcinoma, the neuroendocrine carcinoma, and the adenoma with foci of carcinoma. Nuclear accumulation of p53 protein was immunohistochemically detected in the morphologically high-grade areas of the five cancers harboring a p53 gene missense point mutation. The adenomas, the two frame shift-mutated cancers, and the adenomatous and low-grade cancer areas of mutated carcinomas were immunohistochemically negative. Our data suggest that in ampullary neoplasia 1) p53 mutations are common abnormalities associated with the transformation of adenomas and low-grade cancers into morphologically high-grade carcinomas, and 2) Ki-ras mutations are relatively less frequent and might be restricted to tumors originating from the bile duct component of the ampulla.

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  1. Baczako K., Büchler M., Beger H. G., Kirkpatrick C. J., Haferkamp O. Morphogenesis and possible precursor lesions of invasive carcinoma of the papilla of Vater: epithelial dysplasia and adenoma. Hum Pathol. 1985 Mar;16(3):305–310. doi: 10.1016/s0046-8177(85)80018-6. [DOI] [PubMed] [Google Scholar]
  2. Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
  3. Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
  4. Baker S. J., Markowitz S., Fearon E. R., Willson J. K., Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990 Aug 24;249(4971):912–915. doi: 10.1126/science.2144057. [DOI] [PubMed] [Google Scholar]
  5. Banks L., Matlashewski G., Crawford L. Isolation of human-p53-specific monoclonal antibodies and their use in the studies of human p53 expression. Eur J Biochem. 1986 Sep 15;159(3):529–534. doi: 10.1111/j.1432-1033.1986.tb09919.x. [DOI] [PubMed] [Google Scholar]
  6. Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [DOI] [PubMed] [Google Scholar]
  7. Bos J. L. The ras gene family and human carcinogenesis. Mutat Res. 1988 May;195(3):255–271. doi: 10.1016/0165-1110(88)90004-8. [DOI] [PubMed] [Google Scholar]
  8. Brandt-Rauf P. W., Pincus M. R., Adelson S. Carcinoma of the ampulla of vater. Dig Dis. 1986;4(1):43–48. doi: 10.1159/000171136. [DOI] [PubMed] [Google Scholar]
  9. Bressac B., Kew M., Wands J., Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991 Apr 4;350(6317):429–431. doi: 10.1038/350429a0. [DOI] [PubMed] [Google Scholar]
  10. Buchman V. L., Chumakov P. M., Ninkina N. N., Samarina O. P., Georgiev G. P. A variation in the structure of the protein-coding region of the human p53 gene. Gene. 1988 Oct 30;70(2):245–252. doi: 10.1016/0378-1119(88)90196-5. [DOI] [PubMed] [Google Scholar]
  11. Cattoretti G., Rilke F., Andreola S., D'Amato L., Delia D. P53 expression in breast cancer. Int J Cancer. 1988 Feb 15;41(2):178–183. doi: 10.1002/ijc.2910410204. [DOI] [PubMed] [Google Scholar]
  12. Dawson P. J., Connolly M. M. Influence of site of origin and mucin production on survival in ampullary carcinoma. Ann Surg. 1989 Aug;210(2):173–179. doi: 10.1097/00000658-198908000-00006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Eliyahu D., Michalovitz D., Eliyahu S., Pinhasi-Kimhi O., Oren M. Wild-type p53 can inhibit oncogene-mediated focus formation. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8763–8767. doi: 10.1073/pnas.86.22.8763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M., Hamilton S. R., Preisinger A. C., Thomas G., Kinzler K. W. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
  15. Finlay C. A., Hinds P. W., Levine A. J. The p53 proto-oncogene can act as a suppressor of transformation. Cell. 1989 Jun 30;57(7):1083–1093. doi: 10.1016/0092-8674(89)90045-7. [DOI] [PubMed] [Google Scholar]
  16. Gaidano G., Ballerini P., Gong J. Z., Inghirami G., Neri A., Newcomb E. W., Magrath I. T., Knowles D. M., Dalla-Favera R. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5413–5417. doi: 10.1073/pnas.88.12.5413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gyllensten U. B., Erlich H. A. Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7652–7656. doi: 10.1073/pnas.85.20.7652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Halevy O., Michalovitz D., Oren M. Different tumor-derived p53 mutants exhibit distinct biological activities. Science. 1990 Oct 5;250(4977):113–116. doi: 10.1126/science.2218501. [DOI] [PubMed] [Google Scholar]
  19. Hayashi K., Orita M., Suzuki Y., Sekiya T. Use of labeled primers in polymerase chain reaction (LP-PCR) for a rapid detection of the product. Nucleic Acids Res. 1989 May 11;17(9):3605–3605. doi: 10.1093/nar/17.9.3605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hayashi K. PCR-SSCP: a simple and sensitive method for detection of mutations in the genomic DNA. PCR Methods Appl. 1991 Aug;1(1):34–38. doi: 10.1101/gr.1.1.34. [DOI] [PubMed] [Google Scholar]
  21. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  22. Hsu I. C., Metcalf R. A., Sun T., Welsh J. A., Wang N. J., Harris C. C. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature. 1991 Apr 4;350(6317):427–428. doi: 10.1038/350427a0. [DOI] [PubMed] [Google Scholar]
  23. Iggo R., Gatter K., Bartek J., Lane D., Harris A. L. Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet. 1990 Mar 24;335(8691):675–679. doi: 10.1016/0140-6736(90)90801-b. [DOI] [PubMed] [Google Scholar]
  24. Kinzler K. W., Nilbert M. C., Vogelstein B., Bryan T. M., Levy D. B., Smith K. J., Preisinger A. C., Hamilton S. R., Hedge P., Markham A. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science. 1991 Mar 15;251(4999):1366–1370. doi: 10.1126/science.1848370. [DOI] [PubMed] [Google Scholar]
  25. Knudson A. G., Jr Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985 Apr;45(4):1437–1443. [PubMed] [Google Scholar]
  26. Kozuka S., Tsubone M., Yamaguchi A., Hachisuka K. Adenomatous residue in cancerous papilla of Vater. Gut. 1981 Dec;22(12):1031–1034. doi: 10.1136/gut.22.12.1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lamb P., Crawford L. Characterization of the human p53 gene. Mol Cell Biol. 1986 May;6(5):1379–1385. doi: 10.1128/mcb.6.5.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Levi S., Urbano-Ispizua A., Gill R., Thomas D. M., Gilbertson J., Foster C., Marshall C. J. Multiple K-ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique. Cancer Res. 1991 Jul 1;51(13):3497–3502. [PubMed] [Google Scholar]
  29. Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
  30. Marx J. Many gene changes found in cancer. Science. 1989 Dec 15;246(4936):1386–1388. doi: 10.1126/science.2595361. [DOI] [PubMed] [Google Scholar]
  31. McBride O. W., Merry D., Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci U S A. 1986 Jan;83(1):130–134. doi: 10.1073/pnas.83.1.130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Motojima K., Tsunoda T., Kanematsu T., Nagata Y., Urano T., Shiku H. Distinguishing pancreatic carcinoma from other periampullary carcinomas by analysis of mutations in the Kirsten-ras oncogene. Ann Surg. 1991 Dec;214(6):657–662. doi: 10.1097/00000658-199112000-00003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Murakami Y., Hayashi K., Hirohashi S., Sekiya T. Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res. 1991 Oct 15;51(20):5520–5525. [PubMed] [Google Scholar]
  34. Murakami Y., Hayashi K., Sekiya T. Detection of aberrations of the p53 alleles and the gene transcript in human tumor cell lines by single-strand conformation polymorphism analysis. Cancer Res. 1991 Jul 1;51(13):3356–3361. [PubMed] [Google Scholar]
  35. Neri A., Knowles D. M., Greco A., McCormick F., Dalla-Favera R. Analysis of RAS oncogene mutations in human lymphoid malignancies. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9268–9272. doi: 10.1073/pnas.85.23.9268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nigro J. M., Baker S. J., Preisinger A. C., Jessup J. M., Hostetter R., Cleary K., Bigner S. H., Davidson N., Baylin S., Devilee P. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989 Dec 7;342(6250):705–708. doi: 10.1038/342705a0. [DOI] [PubMed] [Google Scholar]
  37. Oda T., Tsuda H., Scarpa A., Sakamoto M., Hirohashi S. Mutation pattern of the p53 gene as a diagnostic marker for multiple hepatocellular carcinoma. Cancer Res. 1992 Jul 1;52(13):3674–3678. [PubMed] [Google Scholar]
  38. Orita M., Suzuki Y., Sekiya T., Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. doi: 10.1016/0888-7543(89)90129-8. [DOI] [PubMed] [Google Scholar]
  39. Rideout W. M., 3rd, Coetzee G. A., Olumi A. F., Jones P. A. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science. 1990 Sep 14;249(4974):1288–1290. doi: 10.1126/science.1697983. [DOI] [PubMed] [Google Scholar]
  40. Rodrigues N. R., Rowan A., Smith M. E., Kerr I. B., Bodmer W. F., Gannon J. V., Lane D. P. p53 mutations in colorectal cancer. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7555–7559. doi: 10.1073/pnas.87.19.7555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sellner F. Investigations on the significance of the adenoma-carcinoma sequence in the small bowel. Cancer. 1990 Aug 15;66(4):702–715. doi: 10.1002/1097-0142(19900815)66:4<702::aid-cncr2820660419>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  42. Suzuki Y., Orita M., Shiraishi M., Hayashi K., Sekiya T. Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene. 1990 Jul;5(7):1037–1043. [PubMed] [Google Scholar]
  43. Suzuki Y., Sekiya T., Hayashi K. Allele-specific polymerase chain reaction: a method for amplification and sequence determination of a single component among a mixture of sequence variants. Anal Biochem. 1991 Jan;192(1):82–84. doi: 10.1016/0003-2697(91)90188-y. [DOI] [PubMed] [Google Scholar]
  44. Sved J., Bird A. The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4692–4696. doi: 10.1073/pnas.87.12.4692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Takahashi T., D'Amico D., Chiba I., Buchhagen D. L., Minna J. D. Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer. J Clin Invest. 1990 Jul;86(1):363–369. doi: 10.1172/JCI114710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Takahashi T., Nau M. M., Chiba I., Birrer M. J., Rosenberg R. K., Vinocour M., Levitt M., Pass H., Gazdar A. F., Minna J. D. p53: a frequent target for genetic abnormalities in lung cancer. Science. 1989 Oct 27;246(4929):491–494. doi: 10.1126/science.2554494. [DOI] [PubMed] [Google Scholar]
  47. Talbot I. C., Neoptolemos J. P., Shaw D. E., Carr-Locke D. The histopathology and staging of carcinoma of the ampulla of Vater. Histopathology. 1988 Feb;12(2):155–165. doi: 10.1111/j.1365-2559.1988.tb01926.x. [DOI] [PubMed] [Google Scholar]
  48. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  49. Wise L., Pizzimbono C., Dehner L. P. Periampullary cancer. A clinicopathologic study of sixty-two patients. Am J Surg. 1976 Feb;131(2):141–148. doi: 10.1016/0002-9610(76)90087-8. [DOI] [PubMed] [Google Scholar]
  50. Yamaguchi K., Enjoji M. Carcinoma of the ampulla of vater. A clinicopathologic study and pathologic staging of 109 cases of carcinoma and 5 cases of adenoma. Cancer. 1987 Feb 1;59(3):506–515. doi: 10.1002/1097-0142(19870201)59:3<506::aid-cncr2820590326>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  51. Zamboni G., Franzin G., Bonetti F., Scarpa A., Chilosi M., Colombari R., Menestrina F., Pea M., Iacono C., Serio G. Small-cell neuroendocrine carcinoma of the ampullary region. A clinicopathologic, immunohistochemical, and ultrastructural study of three cases. Am J Surg Pathol. 1990 Aug;14(8):703–713. doi: 10.1097/00000478-199008000-00001. [DOI] [PubMed] [Google Scholar]
  52. van den Berg F. M., Tigges A. J., Schipper M. E., den Hartog-Jager F. C., Kroes W. G., Walboomers J. M. Expression of the nuclear oncogene p53 in colon tumours. J Pathol. 1989 Mar;157(3):193–199. doi: 10.1002/path.1711570304. [DOI] [PubMed] [Google Scholar]

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