Amplification/overexpression of a mitotic kinase gene in human bladder cancer.
BACKGROUND
The mitotic kinase-encoding gene STK15/BTAK/ AuroraA is associated with aneuploidy and transformation when overexpressed in mammalian cells. STK15 overexpression activates an unknown oncogenic pathway that involves centrosome amplification and results in missegregation of chromosomes. Because clinical prognosis and tumor aneuploidy are tightly linked in human bladder cancer, we examined whether increased STK15 copy number and protein levels are linked to aneuploidy in bladder cancers.


METHODS
STK15 protein was visualized by immunohistochemistry in 205 formalin-fixed, paraffin-embedded human bladder tumors. STK15 gene copy number was evaluated in 61 tumors by Southern blot hybridization and in 21 of these 61 tumors by fluorescence in situ hybridization (FISH). Copy numbers of chromosomes 3, 17, 20, and 21 were evaluated by FISH with chromosome-specific probes. STK15 expression levels were related to histologic grade, stage, and DNA ploidy of the tumors and to the patients' follow-up data. The chi-square test for association was used to analyze the relationship between STK15 expression and pathologic features. All statistical tests were two-sided.


RESULTS
Tumors with low levels of STK15 amplification (3-4 copies) showed minimal deviation in their chromosome copy number and diploid or near-diploid total nuclear DNA content. Tumors with higher levels of STK15 amplification (>4 copies) had a major increase of chromosome copy number and of their total nuclear DNA content, i.e., exhibited pronounced aneuploidy. Elevated expression of STK15 was strongly associated with parameters of clinical aggressiveness including high histologic grade (P<.001), invasion (P<.001), increased rate of metastasis (P<.001), and decreased metastasis-free (P<.001) and overall (P<.001) survival of patients with bladder cancer.


CONCLUSIONS
STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer.
Sen
Subrata
S
Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Zhou
Hongyi
H
Zhang
Ruo-Dan
RD
Yoon
Dong S
DS
Vakar-Lopez
Funda
F
Ito
Shigemi
S
Jiang
Feng
F
Johnston
Dennis
D
Grossman
H Barton
HB
Ruifrok
Arnout C
AC
Katz
Ruth L
RL
Brinkley
William
W
Czerniak
Bogdan
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015139:Blotting, Southern; D015153:Blotting, Western; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D012189:Retrospective Studies; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases