AIM: To evaluate the expression of epithelial markers of colorectal carcinogenesis in patients with long-term ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) before and after transplantation. METHODS: Eight patients with UC and PSC prior to liver transplantation (PSC-UC), 22 patients with UC after liver transplantation for PSC (OLT), 9 patients with active ulcerative colitis without PSC (UCA), 7 patients with UC in remission (UCR) and 10 controls (N) underwent colonoscopy with multiple biopsies. Specimens were analysed histologically and semi-quantitatively immunohistochemically for p53, Bcl-2 and cyclooxygenase-2 (COX-2) markers. Statistical analysis was performed by Kruskal-Wallis and Fisher's exact tests. RESULTS: PSC-UC had a statistically significantly higher expression of p53 in the nondysplastic mucosa as compared to OLT, UCA, UCR and N (P < 0.05). We also found a statistically significant positive correlation between the incidence of PSC and the expression of p53 (P < 0.001). UCA had a higher p53 expression as compared to UCR. OLT had a significantly lower expression of p53 as compared with PSC-UC (P < 0.001). Bcl-2 had a significant higher bcl-2 expression as compared with controls. No difference in COX-2 expression between PSC-UC, UCR and UCA was found. UCA had higher COX-2 expression as compared to UCR. We also found a statistically significant positive correlation between the expression of COX-2 and p53. Patients after liver transplantation for PSC had a statistically significantly lower expression of the p53 compared with PSC-UC (P < 0.001). PSC-UC had the same inflammatory endoscopic activity as OLT and UCR when evaluated with the Mayo score. CONCLUSION: Our study shows that the nondysplatic mucosa of UC patients with PSC is characterised by a higher expression of the tumour suppressor gene p53, suggesting a higher susceptibility of cancer. This p53 overexpression correlates with the presence of PSC whilst it is not present in patients with UC after liver transplantation for PSC.

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine Videnska 1958 14021 Prague 4 Czech Republic

Zobrazit více v PubMed

Weismüller TJ, Wedemeyer J, Kubicka S, Strassburg CP, Manns MP. The challenges in primary sclerosing cholangitis--aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol. 2008;48 Suppl 1:S38–S57. PubMed

Torres J, Pineton de Chambrun G, Itzkowitz S, Sachar DB, Colombel JF. Review article: colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease. Aliment Pharmacol Ther. 2011;34:497–508. PubMed

Loftus EV, Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR, Jewell DA, Sandborn WJ. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 2005;54:91–96. PubMed PMC

Sokol H, Cosnes J, Chazouilleres O, Beaugerie L, Tiret E, Poupon R, Seksik P. Disease activity and cancer risk in inflammatory bowel disease associated with primary sclerosing cholangitis. World J Gastroenterol. 2008;14:3497–3503. PubMed PMC

Triantafillidis JK, Nasioulas G, Kosmidis PA. Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res. 2009;29:2727–2737. PubMed

Lindberg BU, Broomé U, Persson B. Proximal colorectal dysplasia or cancer in ulcerative colitis. The impact of primary sclerosing cholangitis and sulfasalazine: results from a 20-year surveillance study. Dis Colon Rectum. 2001;44:77–85. PubMed

Kornfeld D, Ekbom A, Ihre T. Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut. 1997;41:522–525. PubMed PMC

Navaneethan U, Venkatesh PG, Lashner BA, Remzi FH, Shen B, Kiran RP. Temporal trends in colon neoplasms in patients with primary sclerosing cholangitis and ulcerative colitis. J Crohns Colitis. 2012;6:845–851. PubMed

Vera A, Gunson BK, Ussatoff V, Nightingale P, Candinas D, Radley S, Mayer A, Buckels JA, McMaster P, Neuberger J, et al. Colorectal cancer in patients with inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Transplantation. 2003;75:1983–1988. PubMed

Karlsen TH, Schrumpf E, Boberg KM. Primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2010;24:655–666. PubMed

Loftus EV, Aguilar HI, Sandborn WJ, Tremaine WJ, Krom RA, Zinsmeister AR, Graziadei IW, Wiesner RH. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology. 1998;27:685–690. PubMed

MacLean AR, Lilly L, Cohen Z, O'Connor B, McLeod RS. Outcome of patients undergoing liver transplantation for primary sclerosing cholangitis. Dis Colon Rectum. 2003;46:1124–1128. PubMed

Drastich P, Wohl P, Kamenar D, Trunecka P, Spicak J. Risk of colorectal cancer in patients with ulcerative colitis after orthotopic liver transplantation for primary sclerosing cholangitis-a single center experience. JCC. 2012;6:s69.

Potack J, Itzkowitz SH. Colorectal cancer in inflammatory bowel disease. Gut Liver. 2008;2:61–73. PubMed PMC

Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, Williams C, Price A, Talbot I, Forbes A. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004;126:451–459. PubMed

Harris AL. Mutant p53--the commonest genetic abnormality in human cancer? J Pathol. 1990;162:5–6. PubMed

Lashner BA, Shapiro BD, Husain A, Goldblum JR. Evaluation of the usefulness of testing for p53 mutations in colorectal cancer surveillance for ulcerative colitis. Am J Gastroenterol. 1999;94:456–462. PubMed

Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789–799. PubMed

Ilyas M, Talbot IC. p53 expression in ulcerative colitis: a longitudinal study. Gut. 1995;37:802–804. PubMed PMC

Sato A, MacHinami R. p53 immunohistochemistry of ulcerative colitis-associated with dysplasia and carcinoma. Pathol Int. 1999;49:858–868. PubMed

Kinra SLP, Mehta CA, Rai LGR. Study of p53 and bcl-2 Oncoproteins in Ulcerative Colitis with Dysplasia. MJAFI. 2005;2:125–129. PubMed PMC

Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011;140:1807–1816. PubMed

Hussain SP, Amstad P, Raja K, Ambs S, Nagashima M, Bennett WP, Shields PG, Ham AJ, Swenberg JA, Marrogi AJ, et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res. 2000;60:3333–3337. PubMed

Paiotti AP, Artigiani Neto R, Forones NM, Oshima CT, Miszputen SJ, Franco M. Immunoexpression of cyclooxygenase-1 and -2 in ulcerative colitis. Braz J Med Biol Res. 2007;40:911–918. PubMed

Romero M, Artigiani R, Costa H, Oshima CT, Miszputen S, Franco M. Evaluation of the immunoexpression of COX-1, COX-2 and p53 in Crohn's disease. Arq Gastroenterol. 2008;45:295–300. PubMed

Agoff SN, Brentnall TA, Crispin DA, Taylor SL, Raaka S, Haggitt RC, Reed MW, Afonina IA, Rabinovitch PS, Stevens AC, et al. The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. Am J Pathol. 2000;157:737–745. PubMed PMC

Brüwer M, Schmid KW, Senninger N, Schürmann G. Immunohistochemical expression of P53 and oncogenes in ulcerative colitis-associated colorectal carcinoma. World J Surg. 2002;26:390–396. PubMed

D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, Lémann M, Marteau P, Rutgeerts P, Schölmerich J, et al. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology. 2007;132:763–786. PubMed

Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317:1625–1629. PubMed

Laurent C, Svrcek M, Flejou JF, Chenard MP, Duclos B, Freund JN, Reimund JM. Immunohistochemical expression of CDX2, β-catenin, and TP53 in inflammatory bowel disease-associated colorectal cancer. Inflamm Bowel Dis. 2011;17:232–240. PubMed

Jackson LM, Wu KC, Mahida YR, Jenkins D, Hawkey CJ. Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa. Gut. 2000;47:762–770. PubMed PMC

Ahrendt SA, Rashid A, Chow JT, Eisenberger CF, Pitt HA, Sidransky D. p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer. J Hepatobiliary Pancreat Surg. 2000;7:426–431. PubMed

Meng F, Yamagiwa Y, Ueno Y, Patel T. Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. J Hepatol. 2006;44:1055–1065. PubMed PMC

Ilyas M, Tomlinson IP, Hanby AM, Yao T, Bodmer WF, Talbot IC. Bcl-2 expression in colorectal tumors: evidence of different pathways in sporadic and ulcerative-colitis-associated carcinomas. Am J Pathol. 1996;149:1719–1726. PubMed PMC

Holzmann K, Weis-Klemm M, Klump B, Hsieh CJ, Borchard F, Gregor M, Porschen R. Comparison of flow cytometry and histology with mutational screening for p53 and Ki-ras mutations in surveillance of patients with long-standing ulcerative colitis. Scand J Gastroenterol. 2001;36:1320–1326. PubMed

Claessen MM, Schipper ME, Oldenburg B, Siersema PD, Offerhaus GJ, Vleggaar FP. WNT-pathway activation in IBD-associated colorectal carcinogenesis: potential biomarkers for colonic surveillance. Cell Oncol. 2010;32:303–310. PubMed PMC

Wong NA, Mayer NJ, MacKell S, Gilmour HM, Harrison DJ. Immunohistochemical assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis-related dysplasia. Histopathology. 2000;37:108–114. PubMed

Rapozo DC, Grinmann AB, Carvalho AT, de Souza HS, Soares-Lima SC, de Almeida Simão T, de Paiva D, Abby F, Albano RM, Pinto LF. Analysis of mutations in TP53, APC, K-ras, and DCC genes in the non-dysplastic mucosa of patients with inflammatory bowel disease. Int J Colorectal Dis. 2009;24:1141–1148. PubMed

Alkim C, Savas B, Ensari A, Alkim H, Dagli U, Parlak E, Ulker A, Sahin B. Expression of p53, VEGF, microvessel density, and cyclin-D1 in noncancerous tissue of inflammatory bowel disease. Dig Dis Sci. 2009;54:1979–1984. PubMed

Gnewuch C, Liebisch G, Langmann T, Dieplinger B, Mueller T, Haltmayer M, Dieplinger H, Zahn A, Stremmel W, Rogler G, et al. Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease. World J Gastroenterol. 2009;15:3134–3141. PubMed PMC

Pardi DS, Loftus EV, Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology. 2003;124:889–893. PubMed

Herszényi L, Farinati F, Miheller P, Tulassay Z. Chemoprevention of colorectal cancer: feasibility in everyday practice? Eur J Cancer Prev. 2008;17:502–514. PubMed

Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994;9:1799–1805. PubMed

Jørgensen KK, Grzyb K, Lundin KE, Clausen OP, Aamodt G, Schrumpf E, Vatn MH, Boberg KM. Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients. Inflamm Bowel Dis. 2012;18:536–545. PubMed