Abstract
Although a close relation of somatic mutations of the adenomatous polyposis coli gene with ampullary carcinomas in familial adenomatous polyposis patients has been reported, the possible association with sporadic ampullary neoplasms has not been fully examined. We have therefore investigated loss of heterozygosity at the adenomatous polyposis coli locus and the mutational status of a portion of the adenomatous polyposis coli gene, including the mutation cluster region, in 17 ampullary carcinomas of non–familial adenomatous polyposis patients. Alteration of the adenomatous polyposis coli gene was found in 8 of 17 (47.1%) cases, as missense or insertion mutations, with or without loss of heterozygosity. Additional investigation of ⁁53 (cxons 5–8) and K–ras (codons 12 and 13) gene mutations revealed a striking mutational pattern of thep53 gene. Nine of the 17 cases demonstrated a total of 12 mutations, 6 clustered at codon 189 and 3 at codon 166. Furthermore, 5 of the 12 mutations were nonsense mutations. Regarding the K–ras gene, 4 of the 17 (23.5%) cases had mutations in codon 12, 3 of the 4 cases being derived from the intraduodenal bile duct. The findings indicate that alterations of the adenomatous polyposis coli and the p53 genes are relatively frequent in sporadic ampullary carcinomas. In particular, the clustering at specific p53 codons might offer an etiological clue to clarify ampullary carcinogenesis. Mutations of the K–ras gene, on the other hand, might be characteristic of intraduodenal bile duct origin.
Keywords: Ampullary carcinoma, APC, p53
Full Text
The Full Text of this article is available as a PDF (544.0 KB).
REFERENCES
- 1. ) Yamaguchi , K. and Enjoji , M.Carcinoma of the ampulla of Vater: a clinicopathologic study and pathologic staging of 109 cases of carcinoma and 5 adenomas . Cancer , 59 , 506 – 515 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Baczako , K. , Buchler , M. , Berger , H. Q. , Kirkpatrick , K. and Otto , H.Morphogenesis and possible precursor lesions of invasive carcinoma of the papilla of Vater, Epithelial dysplasia and adenoma . Hum. Pathol. , 16 , 305 – 310 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Scarpa , A. , Capelli , P. , Zaraboni , G‐ , Oda , T. , Mukai , K. , Bonetti , F. , Martignoni , G. , Lacono , C. , Serio , G. and Hirohashi , S.Neoplasia of the ampulla of Vater. Ki‐ ras and p53 mutations . Am. J. Pathol , 142 , 1163 – 1172 ( 1993. ). [PMC free article] [PubMed] [Google Scholar]
- 4. ) Scarpa , A. , Zamboni , G. , Achilla , A. , Capelli , P. , Bogina , G. , Lacono , C. , Serio , G. and Accolla , R. S.Ras‐family gene mutations in neoplasia of the ampulla of Vater . Int. J. Cancer , 59 , 39 – 42 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Achille , A. , Scupoli , M. T. , Magalini , A. R. , Zamboni , G. , Romanelli , M. G. , Orlandini , S. , Biasi , M. O. , Lemoine , N. R. , Accola , R. S. and Scarpa , A.APC gene mutations and allelic losses in sporadic ampullary tumours: evidence of genetic difference from tumours associated with familial adenomatous polyposis . Int. J. Cancer , 68 , 305 – 312 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Spiegelman , A. D. , Williams , C. B. , Talbot , I. C. , Domizio , P. and Phillips , R. S. K.Upper gastrointestinal cancer in patients with familial adenomatous polyposis . Lancet , 334 , 783 – 785 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Iwama , T. , Mishima , Y. and Utsunomiya , J.The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs . Ann. Surg. , 217 , 101 – 108 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. ) Toyooka , M. , Konishi , M. , Kikuchi‐Yanoshita , R. , Iwama , T. and Miyaki , M.Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal tumors from patients with familial adenomatous polyposis . Cancer Res. , 55 , 3165 – 3170 ( 1995. ). [PubMed] [Google Scholar]
- 9. ) Japanese Society of Biliary Surgery . “General Rules for Surgical and Pathological Studies on Cancer of Biliary Tract. ” 3rd Ed. , pp. 36 – 42 ( 1993. ). Kanehara Co. , Tokyo [Google Scholar]
- 10. ) Impraim , C. C. , Saiki , R. K. , Erlich , H. A. and Teplitz , R. L.Analysis of DNA extracted from formalin‐fixed, paraffin‐embedded tissue by enzymatic amplification and hybridization with sequence‐specific oligonucleotides . Biochem. Biophys. Res. Common. , 142 , 710 – 716 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Miyoshi , Y. , Nagase , H. , Ando , H. , Horii , A. , Ichii , S. , Nakatsuru , S. , Aoki , T. , Miki , Y. , Mori , T. and Nakamura , Y.Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene . Hum. Mol. Genet. , 1 , 229 – 233 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Nigro , J. M. , Baker , S. J. , Preisinger , A. C. , Jessup , J. M. , Hostetter , R. , Cleary , K. , Binger , S. H. , Davidson , N. , Baylin , S. , Devilee , P. , Glover , T. , Collins , F. S. , Weston , A. , Modali , R. , Harris , C. C. and Vogelstein , B.Mutations in the p53 gene occur in diverse human tumor types . Nature , 342 , 705 – 708 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Boynton , R. F. , Blount , P. L. , Yin , J. , Brown , V. L. , Huang , Y. , Tong , Y. , McDaniel , T. , Newkirk , C. , Resau , J. H. , Raskind , W. H. , Haggitt , R. F. , Reid , B. J. and Meltzer , S. J.Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers . Proc. Natl Acad. Sci. USA , 89 , 3385 – 3388 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. ) Miyoshi , Y. , Ando , H. , Nagase , H. , Nishisho , L , Horii , A. , Miki , Y. , Mori , T. , Utsunomiya , J. , Baba , S. , Petersen , G. , Hamilton , S. R. , Kinzler , K. W. , Vogelstein , B. and Nakamura , Y.Germ‐line mutations of the APC gene in 53 familial adenomatous polyposis patients . Proc. Natl Acad. Sci. USA , 89 , 4452 – 4456 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. ) Miyaki , M. , Konishi , M. , Kikuchi‐Yanoshita , R. , Enomoto , M. , Igari , T. , Tanaka , K. , Muraoka , M. , Takahashi , H. , Amada , Y. , Fukayama , M. , Maeda , Y. , Iwama , T. , Mishima , Y. , Mori , T. and Koike , M.Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors . Cancer Res. , 54 , 3011 – 3020 ( 1994. ). [PubMed] [Google Scholar]
- 16. ) Polakis , P.Mutations in the APC gene and their implications for protein structure and function . Curr. Opin. Genet. Dev. , 5 , 66 – 71 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Rubinfeld , B. , Souza , B. , Albert , L , Muller , O. , Chamberlain , S. H. , Masiarz , F. R. , Munemitsu , S. and Polakis , P.Association of the APC gene product with β‐catenin . Science , 262 , 1731 – 1734 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Su , L.‐K. , Vogelstein , B. and Kinzler , K. W.Association of the APC tumor suppressor protein with catenins . Science , 262 , 1734 – 1737 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Hollstein , M. , Sidrausky , D. , Vogelstein , B. and Harris , C. C.p53 mutations in human cancers . Science , 253 , 49 – 53 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Rideout , W. M. , III , Coetzee , G. A. , Olumi , A. F. and Jones , P. A.5‐Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes . Science , 249 , 1288 – 1290 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Sved , J. and Bird , A.The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model . Proc. Natl. Acad. Sci. USA , 87 , 4692 – 4696 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. ) Hsu , I. C. , Metcalf , R. A. , Sun , T. , Welsh , J. A. , Wang , N. J. and Harris , C. C.Mutational hotspot in the p53 gene in hepatocellular carcinomas . Nature , 350 , 427 – 428 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 23. ) Bressac , B. , Kew , M. , Wands , J. and Ozturk , M.Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa . Nature , 350 , 429 – 431 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 24. ) Brandt‐Rauf , P. W. , Pincus , M. R. and Adelson , S.Carcinoma of the ampulla of Vater . Dig. Dis. , 4 , 43 – 48 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 25. ) Nakatsuru , S. , Yanagisawa , A. , Ichii , S. , Tahara , E. , Kato , Y. , Nakamura , Y. and Horii , A.Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet‐ring cell carcinoma . Hum. Mol. Genet. , 1 , 559 – 563 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 26. ) Spiegelman , A. D. , Crofton‐Sleigh , C. , Venett , S. and Phillips , R. K. S.Mutagenicity of bile and duodenal adenomas in familial adenomatous polyposis . Br. J. Surg. , 77 , 878 – 881 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 27. ) Spiegelman , A. D. , Owen , R. W. , Hill , M. H. and Phillips , R. K. S.Biliary bile acid profiles in familial adenomatous polyposis . Br. J. Surg. , 78 , 321 – 325 ( 1991. ). [DOI] [PubMed] [Google Scholar]