Purpose: Malignant tumors show an inherent genetic instability that can be classified as microsatellite instability (MSI) or chromosomal instability (CIN).To elucidate the differences in biological characteristics of bladder cancer between the two types of genetic instability, the expression of the mismatch repair (MMR) proteins, Aurora-A and p53 proteins, the number of centrosomes, numerical aberrations of chromosomes and 20q13, and DNA ploidy were examined in 100 human urothelial carcinomas of the bladder. Experimental Design: Expressions of the MLH1, MSH2, Aurora-A, and p53 proteins and the numbers of centrosomes were immunohistochemically assessed. Numerical aberrations of chromosomes 7, 9, 17, and 20q13 spots were evaluated by fluorescence in situ hybridization, and DNA ploidy was assessed by laser scanning cytometry. Results:The expression levels of the MMR related-proteins decreased in 9 of100 tumors.Tumors with low MLH1 or MSH2 expression (designated as MSI cancers) were not linked with centrosome amplification, Aurora-A overexpression, increased p53 immunoreactivity, 20q13 gain, DNA aneuploidy, and disease progression. MSI cancers showed a favorable prognosis. CIN cancers (49 cases), defined as tumors with a large intercellular variation in centromere copy numbers, were associated more frequently with centrosome amplification, Aurora-A overexpression, increased p53 immunoreactivity, and 20q13 gain than the others (51cases). Tumors with disease progression were included in the CIN cancer group. Conclusions: The present observations suggest that there are differences in the biological characteristics of the two types of genetic instability.Urothelial carcinoma of the bladder is the second most common malignancy of the genitourinary tract (1). Approximately three quarters of all bladder cancers are low-grade and noninvasive superficial tumors. These cancers generally show a favorable prognosis with respect to mortality; however, tumor recurrence and disease progression are found in 50% to 70% and 10% to 20% of tumors, respectively (2). These tumors frequently show an unfavorable disease course. Unfortunately, there are few reliable markers to distinguish these tumors from other kinds of tumors.With tumor progression, genetic aberrations accumulate successively in tumor cells due to the inherent genetic instability of malignant tumors, including urothelial carcinomas. Genetic instability is generally categorized into microsatellite instability (MSI) and chromosomal instability (CIN; ref.3). Defects in mismatch repair (MMR) genes, including hMLH1 and hMSH2, lead directly to the development of MSI. Immunohistochemical determination of MLH1 and MSH2 has been used as a surrogate for MSI determination in colorectal cancer (4 -6). MSI accounts for as many as 10% to 20% of sporadic colorectal carcinomas but the frequency of MSI in bladder cancer is controversial (7 -14).The hypothesis that CIN results from abnormalities of genes implicated in mitosis is widely accepted. Centrosome amplification (15 -17), ...

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