Cancer is a disease that develops slowly. For most solid human tumors there is a 20 year interval between the carcinogen exposure and clinical detection of cancer. In ulcerative colitis (UC), colorectal cancer (CRC) development occurs at a higher rate and speed. For many years it was hypothesized that cancer cells exhibit a mutator phenotype (Loeb et al., 1974). The basic premise is that normal mutation rates are insufficient to account for the multiple mutations observed in cancer cells, and, therefore, changes that increase mutation rates are essential for tumor development. The best example of a mutator phenotype in human cancer has been found in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC), which display microsatellite instability (MSI) due to germline mutations in major mismatch repair (MMR) genes. MSI is regarded as fingerprint of one of the pathways of CRC development, in which processes that determine replication fidelity such as MMR are impaired. Two forms of MSI have been recognized and separated according to the number of mutated microsatellites: MSI-low when only one out of a panel of five microsatellites (typically a dinucleotide repeat) is mutated, and MSI-high when two or more microsatellites (typically both mono- and dinucleotide repeats) are mutated (Boland et al., 1998). In UC, MSI-low was found in dysplastic and cancerous tissue but also in chronically inflamed non-dysplastic mucosa suggesting that impairment of replication fidelity is a key mechanism early in the development of UC-associated CRC (Brentnall et al., 1996). However, investigators have been unable to find evidence for inactivation of DNA MMR genes in these tumors (Noffsinger et al., 1999; Cawkwell et al., 2000). The prevailing hypothesis is that excess amounts of free radicals overwhelm DNA repair pathways leading to accumulation of damaged DNA (Loeb and Loeb, 1999). Perhaps the mechanism responsible for inflammation-associated carcinogenesis is complex and involves a combined increase in the concentration of mutagens together with a inactivation of the DNA repair apparatus by oxidative stress (Chang et al., 2002) or by hMLH1 promoter hypermethylation (Fleisher et al., 2000). An adaptive imbalance in base excision-repair (BER) enzymes was recently identified as a novel mechanism that may contribute to MSI-low (Hofseth et al., 2003).

References:

Loeb,L.A., Springgate,C.F., and Battula,N. (1974). Errors in DNA replication as a basis of malignant changes. Cancer Res 34, 2311-2321.

Boland,C.R., Thibodeau,S.N., Hamilton,S.R., Sidransky,D., Eshleman,J.R., Burt,R.W., Meltzer,S.J., Rodriguez-Bigas,M.A., Fodde,R., Ranzani,G.N., and Srivastava,S. (1998). A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 58, 5248-5257

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. (1996). Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res. 56, 1237-1240.

Noffsinger,A.E., Belli,J.M., Fogt,F., Fischer,J., Goldman,H., and Fenoglio-Preiser,C.M. (1999). A germline hMSH2 alteration is unrelated to colonic microsatellite instability in patients with ulcerative colitis. Hum. Pathol. 30, 8-12.

Cawkwell,L., Sutherland,F., Murgatroyd,H., Jarvis,P., Gray,S., Cross,D., Shepherd,N., Day,D., and Quirke,P. (2000). Defective hMSH2/hMLH1 protein expression is seen infrequently in ulcerative colitis associated colorectal cancers. Gut 46, 367-369.

Chang,C.L., Marra,G., Chauhan,D.P., Ha,H.T., Chang,D.K., Ricciardiello,L., Randolph,A., Carethers,J.M., and Boland,C.R. (2002). Oxidative stress inactivates the human DNA mismatch repair system. Am J Physiol Cell Physiol 283, C148-C154.

Fleisher,A.S., Esteller,M., Harpaz,N., Leytin,A., Rashid,A., Xu,Y., Liang,J., Stine,O.C., Yin,J., Zou,T.T., Abraham,J.M., Kong,D., Wilson,K.T., James,S.P., Herman,J.G., and Meltzer,S.J. (2000). Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res. 60, 4864-4868.

Hofseth,L.J., Khan,M.A., Ambrose,M., Nikolayeva,O., Xu-Welliver,M., Kartalou,M., Hussain,S.P., Roth,R.B., Zhou,X., Mechanic,L.E., Zurer,I., Rotter,V., Samson,L.D., and Harris,C.C. (2003). The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. J. Clin Invest 112, 1887-1894.