Overexpression of the Mitotic Checkpoint Genes BUB1 and BUBR1 is Associated with Genomic Complexity in Clear Cell Kidney Carcinomas

Background : A defective mitotic checkpoint has been proposed to contribute to chromosomal instability (CIN). We have previously shown that expression changes of the mitotic arrest deficiency (MAD) gene family plays a role in renal cell cancer (RCC) characterized by numerical chromosomal changes, namely papillary and chromophobe carcinomas, but nothing is known about the expression of mitotic checkpoint genes in the clear cell histotype (ccRCC). Methods : We analyzed the mRNA expression levels of the major mitotic checkpoint genes of the budding uninhibited by benzimidazole family ( BUB1 , BUBR1 , BUB3 ) and of the MAD gene family ( MAD1 , MAD2L1 , MAD2L2 ) by real-time quantitative PCR in 39 ccRCC and in 36 normal kidney tissue samples.We have additionally analyzed these tumors by comparative genomic hybridization (CGH) in order to evaluate the relationship between mitotic checkpoint defects and the pattern of chromosome changes in this subset of RCC. Results : BUB1 , BUBR1 , MAD1 and MAD2L1 showed significant expression differences in tumor tissue compared to controls ( BUB1 , BUBR1 and MAD2L1 were overexpressed, whereas MAD1 was underexpressed). Overexpression of BUB1 and BUBR1 was significantly correlated with the number of genomic copy number changes ( p < 0.001 for both genes) and with Furhman grade of the tumors ( p = 0.006 and p = 0.005, respectively). Conclusions : We conclude that BUB1 and BUBR1 overexpression plays a role in cytogenetic and morphologic progression of ccRCC.