TY - JOUR
T1 - Amplification/overexpression of a mitotic kinase gene in human bladder cancer
AU - Sen, Subrata
AU - Zhou, Hongyi
AU - Zhang, Ruo Dan
AU - Yoon, Dong S.
AU - Vakar-Lopez, Funda
AU - Ito, Shigemi
AU - Jiang, Feng
AU - Johnston, Dennis
AU - Grossman, H. Barton
AU - Ruifrok, Arnout C.
AU - Katz, Ruth L.
AU - Brinkley, William
AU - Czerniak, Bogdan
PY - 2002/9/4
Y1 - 2002/9/4
N2 - 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 chisquare 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. Conclusion: 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.
AB - 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 chisquare 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. Conclusion: 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.
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U2 - 10.1093/jnci/94.17.1320
DO - 10.1093/jnci/94.17.1320
M3 - Article
C2 - 12208897
AN - SCOPUS:0037019736
SN - 0027-8874
VL - 94
SP - 1320
EP - 1329
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 17
ER -