Abstract
Two cases of ulcerative colitis (UC)‐associated carcinoma or dysplasia and morphologically non‐neoplastic mucosa with p53 protein overexpression (MNNM‐p53OE) were selected. DNA was extracted from the paraffin blocks of these lesions and exons 5‐8 of the p53 gene were analyzed by PCR and direct sequencing. In addition, mutations in K‐ras codon 12 were analyzed by PCR‐RFLP methods. MNNM‐p53OE was located surrounding and adjoining a coexisting carcinoma and/or dysplasia. A p53 mutation was detected in 12/22 (54.5%) MNNM‐p53OE samples, 4/8 (50%) dysplasia samples and 8/8 (100%) carcinoma samples. The/j53 mutations detected in MNNM‐p53OE were identical to those demonstrated in the adjoining carcinoma and/or dysplasia. No K‐ras codon 12 mutation was detected in any of the samples. These results indicate that MNNM‐p53OE may share an identical clonal linkage with a coexisting carcinoma and/or dysplasia, and may be an initial and submorphological form of UC‐associated neoplasia. Recognition of MNNM‐p53OE in biopsy specimens may help to identify patients with UC at risk of developing colorectal carcinoma.
Keywords: Ulcerative colitis, Colorectal cancer, Dysplasia, p53, K‐ras
Full Text
The Full Text of this article is available as a PDF (2.4 MB).
References
- 1.Ekbom , A. , Helmick , C. , Zack , M . and Adami , H.‐O . Ulcerative colitis and colorectal cancer. A population‐based study . N. Engl. J. Med. , 323 , 1228 – 1233 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 2.Riddell , R. H. , Goldman , H. , Ransohoff , D. R , Appleman , H. D. , Fenoglio , C. M. , Haggitt , R. C. , Ahren , C. , Correa , P. , Hamilton , S. R. , Morson , B. C. , Sommers , S. C . and Yardley , J. H . Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applica‐.tions . Hum. Pathol , 14 , 931 – 968 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 3.Lane , D. P . p53, guardian of the genome . Nature , 358 , 15 – 16 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 4.Hollstein , M. , Sidransky , D. , Vogelstein , B . and Harris , C. C . p53 mutations in human cancers . Science , 253 , 49 – 53 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 5.Vogelstein , B. , Fearon , E. R. , Hamilton , S. R. , Kern , S. E. , Preisinger , A. C. , Leppert , M. , Nakamura , Y. , White , R. , Smits , A. M. M . and Bos , J. L . Genetic alterations during colorectal‐tumor development . N. Engl. J. Med. , 319 , 525 – 532 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 6.Fearon , E. R . and Vogelstein , B . A genetic model for colo‐rectal tumorigenesis . Cell , 61 , 759 – 767 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 7.Brentall , T. A. , Chrispin , D. A. , Rabinovitch , P. S. , Haggitt , R. C. , Rubin , C. E. , Stevens , A. C . and Burmer , G. C . Mutations in the p53 gene; an early marker of neoplastic progression in ulcerative colitis . Gastroenterology , 107 , 369 – 378 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 8.Harpaz , N. , Peck , A. L. , Yin , J. , Fiel , L , Hontanosas , M. , Tong , T. R. , Laurin , J. N. , Abraham , J. M. , Greenwald , B. D . and Meltzer , S. J . p53 protein expression in ulcerative colitis‐associated colorectal dysplasia and carcinoma . Hum. Pathol , 25 , 1069 – 1074 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 9.Holzmann , K. , Klump , B. , Borchard , F. , Hsieh , C. J. , Kuhn , A. , Gaco , V. , Gregor , M . and Porschen , R . Comparative analysis of histology, DNA content, p53 and Ki‐ras mutations in colectomy specimens with long‐standing ulcerative colitis . Int. J. Cancer , 30 , 1 – 6 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 10.Burmer , G. C. , Rabinovitch , P. S. , Haggitt , R. C. , Crispin , D. A. , Brentnall , T. A. , Kolli , V. R. , Stevens , A. C . and Rubin , C. E . Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele . Gastroenterology , 103 , 1602 – 1610 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 11.Fogt , F. , Vortmeyer , A. O. , Goldman , H. , Giordano , T. J. , Jerino , M. J . and Zhuang , Z . Comparison of genetic alterations in colonic adenoma and ulcerative colitis‐associated dysplasia and carcinoma . Hum. Pathol , 29 , 131 – 136 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 12.Finlay , C. A. , Hinds , P. W. , Tan , T. H. , Eliyahu , D. , Oren , M . and Levine , A. J . Activating mutations for transformation by p53 produce a gene product that forms an hsc70‐p53 complex with an altered half‐life . Mol. Cell. Biol. , 8 , 531 – 539 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Baas , I. O. , Mulder , J. W. R. , Offerhaus , G. J. , Vogelstein , B . and Hamilton , S. R . An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms . J. Pathol , 172 , 5 – 12 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 14.Ajioka , Y. , Watanabe , H . and Matsuda , K . Over‐expression of p53 protein in neoplastic changes in ulcerative colitis: immunohistochemical study . J. Gastroenterol , 30 , 33 – 35 ( 1995. ). [PubMed] [Google Scholar]
- 15.Klump , B. , Holzmann , K. , Kuhn , A. , Borchard , F. , Sarbia , M. , Gregor , M . and Porschen , R . Distribution of cell population with DNA aneuploidy and p53 protein expression in ulcerative colitis . Eur. J. Gastroenterol Hepatol , 9 , 789 – 794 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 16.Taylor , H. W. , Boyle , M. , Smith , S. C. , Bustin , S . and Williams , N. S . Expression of p53 in colorectal cancer and dysplasia complicating ulcerative colitis . Br. J. Surg. , 80 , 442 – 444 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 17.Matsuda , K. , Watanabe , H. , Jass , J. R. , Ajioka , Y. , Kobayashi , M. , Saito , H. , Sasaki , M. , Yasuda , K . and Kuwabara , A . Frequency of p53‐positive cells in differing histological phases of ulcerative colitis . Acta Med. Biol. , 43 , 197 – 203 ( 1995. ). [Google Scholar]
- 18.Krishna , M. , Woda , B. , Savas , L. , Baker , S . and Banner , B . Expression of p53 antigen in inflamed and regenerated mucosa in ulcerative colitis and Crohn's disease . Mod. Pathol , 8 , 654 – 657 ( 1995. ). [PubMed] [Google Scholar]
- 19.Matsuda , K. , Watanabe , H. , Ajioka , Y. , Kobayashi , M. , Saito , H. , Sasaki , M. , Yasuda , K. , Kuwabara , A. , Nishikura , K . and Muto , T . Ulcerative colitis with overexpression of p53 preceding overt histological abnormalities of the epithelium . J. Gastroenterol , 31 , 860 – 867 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 20.Kim , H. J . and Chang , S. K . p53 mutation in patients with ulcerative colitis in rectal biopsy . Korean Intern. Med. , 13 , 110 – 116 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Watanabe , H. , Ajioka , Y. , Yamaguchi , M. , Noda , Y. , Honma , T . and Motoyama , T . New histological criteria of colorectal adenoma and carcinoma . Stomach Intestine , 24 , 253 – 259 ( 1989. ) ( in Japanese ). [Google Scholar]
- 22.Schlemper , R. J. , Itabashi , M. , Kato , Y. , Lewin , K. J. , Riddell , R. H. , Shimoda , T. , Sipponen , P. , Stolte , M . and Watanabe , H . Differences in the diagnostic criteria used by Japanese and Western pathologists to diagnose colorectal carcinoma . Cancer , 82 , 60 – 69 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 23.Yokoyama , N. , Hitomi , J. , Watanabe , H. , Ajioka , Y. , Pruyas , M. , Serra , L , Shirai , Y . and Hatakeyama , K . Mutations of p53 in gallbladder carcinomas in high‐incidence area of Japan and Chile . Cancer Epidemiol. Biomarker Prev. , 7 , 297 – 310 ( 1998. ). [PubMed] [Google Scholar]
- 24.Ooshima , S. , Shimizu , Y . and Takahama , M . Detection of c‐Ki‐ras gene mutation in paraffin sections of adenocarcinoma and atypical bronchioalveolar cell hyperplasia of human lung . Virchows Arch. , 424 , 129 – 134 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 25.Kuwabara , A. , Watanabe , H. , Ajioka , Y. , Yasuda , K. , Saito , H. , Matsuda , K. , Kijima , H . and Hatakeyama , K . Alteration of p53 clonality accompanying colorectal cancer progression . Jpn. J. Cancer Res. , 89 , 40 – 46 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Ren , Z. P. , Hedrum , A. , Ponten , A. , Nister , M. , Ahmadian , A. , Lundeberg , J. , Uhlen , M . and Ponten , J . Human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non‐neoplastic keratinocytes . Oncogene , 12 , 765 – 773 ( 1996. ). [PubMed] [Google Scholar]
- 27.Weinberg , W. C. , Azzoli , C. G. , Chapman , K. , Levine , A. J . and Yuspa , S. H . p53‐mediated transcriptional activity increases in differentiating epidermal keratinocytes in association with decreased p53 protein . Oncogene , 15 , 2271 – 2279 ( 1995. ). [PubMed] [Google Scholar]
- 28.Matsuda , K. , Watanabe , H. , Ohta , T . and Ajioka , Y . Over expressed p53 protein and cell‐proliferative activity disappear or remarkably decrease in neoplastic CGA‐positive endocrine and Paneth cells in cancer or dysplasia of ulcerative colitis . Jpn. J. Gastroenterol , 92 , 1922 – 1928 ( 1995. ) ( in Japanese with English abstract ). [PubMed] [Google Scholar]
- 29.Willenbucher , R. F. , Zelman , S. J. , Ferrell , L. D. , Moore , D. H . and Waldman , F. M . Chromosomal alterations in ulcerative colitis‐related neoplastic progression . Gastroenterology , 113 , 791 – 801 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 30.Brentnall , T. A. , Crispin , D. A. , Bronner , M. P. , Cherian , S. P. , Hueffed , M. , Rabinovitch , P. S. , Rubin , C. E. , Haggitt , R. C . and Boland , C. R . Microsatellite instability in non‐neoplastic mucosa from patients with chronic ulcerative colitis . Cancer Res. , 56 , 1237 – 1240 ( 1996. ). [PubMed] [Google Scholar]
- 31.Noffsinger , A. E. , Miller , M. A. , Cusi , M. V . and Fenoglio‐Preiser , C. M . The pattern of cell proliferation in neoplastic and nonneoplastic lesions of ulcerative colitis . Cancer , 78 , 2307 – 2312 ( 1996. ). [PubMed] [Google Scholar]
- 32.Kinouchi , Y. , Hiwatashi , N. , Chida , M. , Nagashima , F. , Takagi , S. , Maekawa , H . and Toyota , T . Telomere shortening in the colonic mucosa of patients with ulcerative colitis . J. Gastroenterol. , 33 , 343 – 348 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 33.Bos , J. L . The ras gene family and human carcinogenesis . Mutat. Res. , 195 , 255 – 271 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 34.Burner , G. C. , Levine , D. S. , Kulander , B. G. , Haggitt , R. C. , Rubin , C. E . and Rabinovitch , P. S . c‐Ki‐ras mutations in chronic ulcerative colitis and sporadic colon carcinoma . Gastroenterology , 99 , 416 – 420 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 35.Chaubert , P. , Benhattar , J. , Saraga , E . and Costa , J . K‐ras mutations and p53 alterations in neoplastic and nonneoplastic lesions associated with longstanding ulcerative colitis . Am. J. Pathol , 144 , 767 – 775 ( 1994. ). [PMC free article] [PubMed] [Google Scholar]