Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

Mutation of human homologues of DNA mismatch repair (MMR) genes in tumours has been shown to be associated with the phenomenon of microsatellite insta bility (MSI). Several studies have reported the occurrence of MSI in bladde r cancer, but evidence of involvement of MMR genes in the pathogenesis of t his cancer is still unclear. We therefore utilized quantitative immunohisto chemical (IHC) image analysis and PCR-based allelotype analysis to determin e hMLH1 and hMSH2 genes alteration in a cohort of Egyptian bladder cancer s amples. IHC analysis of 24 TCC and 12 SCC revealed marked- intra and intert umour heterogeneity in the levels of expression of the two MMR proteins. On e TCC lost MLH1 expression and one lost MSH2, (1/24, 4%), and one SCC lost MSH2 (1/12, 8%). A large proportion of analysed tumours revealed a percenta ge positivity of less than 50% far MLH1 and MSH2 expression (44% and 69%, r espectively). Complete loss of heterozygosity in three dinucleotide repeats lying within, or in close proximity to, hMLH1 and hMSH2 was rare (2/57, (4 %) for MLH1; and 1/55, (2%) for MSH2), however allelic imbalance was detect ed in 11/57 (hMLH1) and 10/55 (hMSH2) at any of the informative microsatell ite loci. These alterations in structure and expression of DNA MMR genes su ggest their possible involvement in the tumorigenesis and/or progression of bladder cancer. (C) 2001 Cancer Research Campaign.