Detection of K-ras mutations in mucinous pancreatic duct hyperplasia from a patient with a family history of pancreatic carcinoma (original) (raw)

. 1994 May;144(5):889–895.

Abstract

Mutations in the K-ras oncogene and in the p53 tumor suppressor gene are commonly identified in sporadic cases of pancreatic adenocarcinoma. Although these genes might serve as useful markers for early diagnosis of pancreatic carcinoma in patients at risk for the development of this disease, familial pancreatic carcinomas have not been studied for these mutations. We recently had the opportunity to examine a pancreas prophylactically removed from a patient with a strong family history of pancreatic carcinoma. This gave us the unique opportunity to study the early events in the development of familial adenocarcinoma of the pancreas. Histopathological examination of the pancreas revealed multifocal papillary and nonpapillary mucinous duct hyperplasia. Seven of these foci were microdissected and analyzed for K-ras and p53 mutations. The K-ras mutations were detected by combined mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis and characterized further by allele-specific oligonucleotide hybridization. Five of the seven duct lesions harbored activating point mutations in codon 12 of K-ras; a G to A transition was found in four and a G to C transversion in one. In contrast, these lesions did not harbor detectable p53 mutations as determined by denaturing gradient gel electrophoresis of exons 5 to 8, nor was there overexpression of the p53 protein as determined by immunohistochemistry. These findings suggest that mutations in K-ras represent an early event in the pathogenesis of pancreatic carcinoma. In addition, monitoring of patients with a strong family history of pancreatic carcinoma for K-ras mutations may identify patients at risk for the development of invasive carcinoma.

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Selected References

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  1. Almoguera C., Shibata D., Forrester K., Martin J., Arnheim N., Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988 May 20;53(4):549–554. doi: 10.1016/0092-8674(88)90571-5. [DOI] [PubMed] [Google Scholar]
  2. Baker S. J., Preisinger A. C., Jessup J. M., Paraskeva C., Markowitz S., Willson J. K., Hamilton S., Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990 Dec 1;50(23):7717–7722. [PubMed] [Google Scholar]
  3. Barton C. M., Staddon S. L., Hughes C. M., Hall P. A., O'Sullivan C., Klöppel G., Theis B., Russell R. C., Neoptolemos J., Williamson R. C. Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer. 1991 Dec;64(6):1076–1082. doi: 10.1038/bjc.1991.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boring C. C., Squires T. S., Tong T. Cancer statistics, 1991. CA Cancer J Clin. 1991 Jan-Feb;41(1):19–36. doi: 10.3322/canjclin.41.1.19. [DOI] [PubMed] [Google Scholar]
  5. Cubilla A. L., Fitzgerald P. J. Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res. 1976 Jul;36(7 Pt 2):2690–2698. [PubMed] [Google Scholar]
  6. Danes B. S., Lynch H. T. A familial aggregation of pancreatic cancer. An in vitro study. JAMA. 1982 May 28;247(20):2798–2802. [PubMed] [Google Scholar]
  7. Ehrenthal D., Haeger L., Griffin T., Compton C. Familial pancreatic adenocarcinoma in three generations. A case report and a review of the literature. Cancer. 1987 May 1;59(9):1661–1664. doi: 10.1002/1097-0142(19870501)59:9<1661::aid-cncr2820590923>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  8. Ghadirian P., Boyle P., Simard A., Baillargeon J., Maisonneuve P., Perret C. Reported family aggregation of pancreatic cancer within a population-based case-control study in the Francophone community in Montreal, Canada. Int J Pancreatol. 1991 Nov-Dec;10(3-4):183–196. doi: 10.1007/BF02924156. [DOI] [PubMed] [Google Scholar]
  9. Ghadirian P., Simard A., Baillargeon J. Cancer of the pancreas in two brothers and one sister. Int J Pancreatol. 1987 Oct-Dec;2(5-6):383–391. doi: 10.1007/BF02788437. [DOI] [PubMed] [Google Scholar]
  10. Grünewald K., Lyons J., Fröhlich A., Feichtinger H., Weger R. A., Schwab G., Janssen J. W., Bartram C. R. High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer. 1989 Jun 15;43(6):1037–1041. doi: 10.1002/ijc.2910430614. [DOI] [PubMed] [Google Scholar]
  11. Hinds P., Finlay C., Levine A. J. Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J Virol. 1989 Feb;63(2):739–746. doi: 10.1128/jvi.63.2.739-746.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hruban R. H., van Mansfeld A. D., Offerhaus G. J., van Weering D. H., Allison D. C., Goodman S. N., Kensler T. W., Bose K. K., Cameron J. L., Bos J. L. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993 Aug;143(2):545–554. [PMC free article] [PubMed] [Google Scholar]
  13. Kahn S. M., Jiang W., Culbertson T. A., Weinstein I. B., Williams G. M., Tomita N., Ronai Z. Rapid and sensitive nonradioactive detection of mutant K-ras genes via 'enriched' PCR amplification. Oncogene. 1991 Jun;6(6):1079–1083. [PubMed] [Google Scholar]
  14. Klöppel G., Bommer G., Rückert K., Seifert G. Intraductal proliferation in the pancreas and its relationship to human and experimental carcinogenesis. Virchows Arch A Pathol Anat Histol. 1980;387(2):221–233. doi: 10.1007/BF00430702. [DOI] [PubMed] [Google Scholar]
  15. Kozuka S., Sassa R., Taki T., Masamoto K., Nagasawa S., Saga S., Hasegawa K., Takeuchi M. Relation of pancreatic duct hyperplasia to carcinoma. Cancer. 1979 Apr;43(4):1418–1428. doi: 10.1002/1097-0142(197904)43:4<1418::aid-cncr2820430431>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  16. Lemoine N. R., Jain S., Hughes C. M., Staddon S. L., Maillet B., Hall P. A., Klöppel G. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology. 1992 Jan;102(1):230–236. doi: 10.1016/0016-5085(92)91805-e. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Lowenfels A. B., Maisonneuve P., Cavallini G., Ammann R. W., Lankisch P. G., Andersen J. R., Dimagno E. P., Andrén-Sandberg A., Domellöf L. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993 May 20;328(20):1433–1437. doi: 10.1056/NEJM199305203282001. [DOI] [PubMed] [Google Scholar]
  19. Lynch H. T., Fitzsimmons M. L., Smyrk T. C., Lanspa S. J., Watson P., McClellan J., Lynch J. F. Familial pancreatic cancer: clinicopathologic study of 18 nuclear families. Am J Gastroenterol. 1990 Jan;85(1):54–60. [PubMed] [Google Scholar]
  20. Lynch H. T., Fusaro L., Lynch J. F. Familial pancreatic cancer: a family study. Pancreas. 1992;7(5):511–515. doi: 10.1097/00006676-199209000-00001. [DOI] [PubMed] [Google Scholar]
  21. Lynch H. T., Voorhees G. J., Lanspa S. J., McGreevy P. S., Lynch J. F. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br J Cancer. 1985 Aug;52(2):271–273. doi: 10.1038/bjc.1985.187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mariyama M., Kishi K., Nakamura K., Obata H., Nishimura S. Frequency and types of point mutation at the 12th codon of the c-Ki-ras gene found in pancreatic cancers from Japanese patients. Jpn J Cancer Res. 1989 Jul;80(7):622–626. doi: 10.1111/j.1349-7006.1989.tb01687.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Midgley C. A., Fisher C. J., Bártek J., Vojtesek B., Lane D., Barnes D. M. Analysis of p53 expression in human tumours: an antibody raised against human p53 expressed in Escherichia coli. J Cell Sci. 1992 Jan;101(Pt 1):183–189. doi: 10.1242/jcs.101.1.183. [DOI] [PubMed] [Google Scholar]
  24. Myers R. M., Maniatis T., Lerman L. S. Detection and localization of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol. 1987;155:501–527. doi: 10.1016/0076-6879(87)55033-9. [DOI] [PubMed] [Google Scholar]
  25. Nagata Y., Abe M., Motoshima K., Nakayama E., Shiku H. Frequent glycine-to-aspartic acid mutations at codon 12 of c-Ki-ras gene in human pancreatic cancer in Japanese. Jpn J Cancer Res. 1990 Feb;81(2):135–140. doi: 10.1111/j.1349-7006.1990.tb02539.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Obara T., Saitoh Y., Maguchi H., Ura H., Kitazawa S., Koike Y., Okamura K., Namiki M. Multicentric development of pancreatic intraductal carcinoma through atypical papillary hyperplasia. Hum Pathol. 1992 Jan;23(1):82–85. doi: 10.1016/0046-8177(92)90018-x. [DOI] [PubMed] [Google Scholar]
  27. Scarpa A., Capelli P., Mukai K., Zamboni G., Oda T., Iacono C., Hirohashi S. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol. 1993 May;142(5):1534–1543. [PMC free article] [PubMed] [Google Scholar]
  28. Shimizu M., Itoh H., Okumura S., Hashimoto K., Hanioka K., Ohyanagi H., Yamamoto M., Kuroda Y., Tanaka T., Saitoh Y. Papillary hyperplasia of the pancreas. Hum Pathol. 1989 Aug;20(8):806–807. doi: 10.1016/0046-8177(89)90077-4. [DOI] [PubMed] [Google Scholar]
  29. Sidransky D., Tokino T., Hamilton S. R., Kinzler K. W., Levin B., Frost P., Vogelstein B. Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science. 1992 Apr 3;256(5053):102–105. doi: 10.1126/science.1566048. [DOI] [PubMed] [Google Scholar]
  30. Smit V. T., Boot A. J., Smits A. M., Fleuren G. J., Cornelisse C. J., Bos J. L. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res. 1988 Aug 25;16(16):7773–7782. doi: 10.1093/nar/16.16.7773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tada M., Omata M., Kawai S., Saisho H., Ohto M., Saiki R. K., Sninsky J. J. Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res. 1993 Jun 1;53(11):2472–2474. [PubMed] [Google Scholar]
  32. Tada M., Omata M., Ohto M. Ras gene mutations in intraductal papillary neoplasms of the pancreas. Analysis in five cases. Cancer. 1991 Feb 1;67(3):634–637. doi: 10.1002/1097-0142(19910201)67:3<634::aid-cncr2820670318>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  33. Warshaw A. L., Fernández-del Castillo C. Pancreatic carcinoma. N Engl J Med. 1992 Feb 13;326(7):455–465. doi: 10.1056/NEJM199202133260706. [DOI] [PubMed] [Google Scholar]
  34. Yanagisawa A., Ohtake K., Ohashi K., Hori M., Kitagawa T., Sugano H., Kato Y. Frequent c-Ki-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res. 1993 Mar 1;53(5):953–956. [PubMed] [Google Scholar]
  35. van Mansfeld A. D., Bos J. L. PCR-based approaches for detection of mutated ras genes. PCR Methods Appl. 1992 May;1(4):211–216. doi: 10.1101/gr.1.4.211. [DOI] [PubMed] [Google Scholar]
  36. van den Berg F. M., Baas I. O., Polak M. M., Offerhaus G. J. Detection of p53 overexpression in routinely paraffin-embedded tissue of human carcinomas using a novel target unmasking fluid. Am J Pathol. 1993 Feb;142(2):381–385. [PMC free article] [PubMed] [Google Scholar]