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).
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.
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
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.
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.