Decreased DOC-2/DAB2 Expression in Urothelial Carcinoma of the Bladder

Purpose: DOC-2/DAB2 (differentially expressed in ovarian carcinoma-2/disabled-2), a potential tumor suppressor gene, is underexpressed in several cancers. Little is known about the expression of this gene in urothelial carcinoma of the bladder (UCB). We profiled DOC-2/DAB2 expression in mouse and human normal and neoplastic urothelia. Experimental Design: Immunohistochemical staining for DOC-2/DAB2 was carried out on tissue specimens from two transgenic mouse models with urothelium-specific molecular alterations and on a tissue microarray containing cores from 9 normal controls, 44 patients who underwent transurethral resection of the bladder tumor (TURBT), 195 patients who underwent radical cystectomy for UCB, and 39 lymph nodes with metastatic UCB. Results: Normal mouse urothelium stained uniformly with DOC-2/DAB2. Weaker staining was observed in low-grade, superficial papillary bladder tumors from transgenic mice harboring constitutively active Ha-Ras , whereas carcinoma in situ –like lesions and high-grade bladder tumors from transgenic mice expressing a SV40 T antigen completely lacked DOC-2/DAB2 expression. In human tissues, DOC-2/DAB2 expression was decreased in 11% of normal bladder specimens, 59% of TURBT specimens, 65% of radical cystectomy specimens, and 77% of the metastatic lymph node specimens. Decreased DOC-2/DAB2 expression was associated with advanced pathologic stage ( P = 0.023), lymph node metastases ( P = 0.050), and lymphovascular invasion ( P < 0.001). In univariable, but not in multivariable analysis, decreased DOC-2/DAB2 was associated with an increased probability of bladder cancer recurrence (log-rank test, P = 0.020) and bladder cancer–specific mortality (log-rank test, P = 0.023). Conclusions: Decreased DOC-2/DAB2 expression seems to occur early in bladder tumorigenesis and becomes more prominent in advanced stages of UCB.