6p22.3 amplification as a biomarker and potential therapeutic target of advanced stage bladder cancer
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He Shen1,*, Carl D. Morrison2,*, Jianmin Zhang1, Willie Underwood III3, Nuo Yang 1, Costa Frangou1, Kevin Eng4, Karen Head 2, Roni J. Bollag7, Sravan K. Kavuri7, Amyn M. Rojiani7, Yingwei Li1, Li Yan4, Annette Hill2, Anna Woloszynska-Read5, Jianmin Wang4, Song Liu4, Donald L. Trump6 & Candace S. Johnson5
1 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263
2 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263
3 Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263
4 Center for Biostatistics, Roswell Park Cancer Institute, Buffalo, NY 14263
5 Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263
6 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263
7 Department of Pathology, Georgia Regents University, Augusta, GA
* Equal contribution
Jianmin Zhang, email:
Keywords: bladder cancer, chromosome 6p22, FISH, outcome, survival
Received: September 9, 2013 Accepted: October 29, 2013 Published: October 29, 2013
Genetic and epigenetic alterations have been identified as to contribute directly or indirectly to the generation of transitional cell carcinoma of the urinary bladder (TCC-UB). In a comparative fashion much less is known about copy number alterations in TCC-UB, but it appears that amplification of chromosome 6p22 is one of the most frequent changes. Using fluorescence in situ hybridization (FISH) analyses, we evaluated chromosomal 6p22 amplification in a large cohort of bladder cancer patients with complete surgical staging and outcome data. We have also used shRNA knockdown candidate oncogenes in the cell based study. We found that amplification of chromosome 6p22.3 is significantly associated with the muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) (22%) in contrast to superficial TCC-UB (9%) (p=7.2-04). The rate of 6p22.3 amplification in pN>1 patients (32%) is more than twice that in pN0 (16%) patients (p=0.05). Interestingly, we found that 6p22.3 amplification is as twice as high (p=0.0201) in African American (AA) than European American (EA) TCC-UB patients. Moreover, we showed that the expression of some candidate genes (E2F3, CDKAL1 and Sox4) in the 6p22.3 region is highly correlated with the chromosomal amplification. In particular, knockdown of E2F3 inhibits cell proliferation in a 6p22.3-dependent manner, whereas knockdown of CDKAL1 and Sox4 has no effect on cell proliferation. Using gene expression profiling, we further identified some common as well as distinctive subset targets of the E2F3 family members. In summary, our data indicate that E2F3 is a key regulator of cell proliferation in a subset of bladder cancer and the 6p22.3 amplicon is a biomarker of aggressive phenotype in this tumor type.
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