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.
Pinto
Mafalda
M
Department of Genetics, Portuguese Oncology Institute, 4200-072 Porto, Portugal.
Vieira
Joana
J
Ribeiro
Franclim R
FR
Soares
Maria J
MJ
Henrique
Rui
R
Oliveira
Jorge
J
Jerónimo
Carmen
C
Teixeira
Manuel R
MR
D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D064246:Mad2 Proteins; D009687:Nuclear Proteins / Q000096:biosynthesis; D009693:Nucleic Acid Hybridization; D000075223:Poly-ADP-Ribose Binding Proteins; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
C489444:BUB3 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases