Vol. 179, No. 4, Supplement, Monday, May 19, 2008 THE JOURNAL OF UROLOGY® 263

753MSH2 MUTATIONS AND BLADDER CANCER RISK: FAMILY MEMBERS OF HEREDITARY NONPOLYPOSIS COLORECTAL CANCER PATIENTS WITH MSH2 MUTATIONS ARE AT INCREASED RISK NOT ONLY FOR UPPER TRACT TRANSITIONAL CELL CARCINOMA BUT ALSO BLADDER CANCERSean Skeldon, K Semotiuk, Steve Gallinger, Neil E Fleshner, Michael A S Jewett, M Cotterchio, Alexandre R Zlotta*. Toronto, ON, Canada.

INTRODUCTION AND OBJECTIVE: Several studies have reported abnormal MSH2 immunohistochemical expression in bladder tumours, a mismatch repair gene mutated in hereditary nonpolyposis colorectal cancer (HNPCC) families. A correlation between HNPCC and upper tract transitional cell carcinoma (UTCC) had been previously described, but information about bladder cancer risk in MSH2 mutations within these families has not been conclusive. In this study, the risk of

Toronto Familial Gastrointestinal Cancer Registry (FGICR), and in particular those with MSH2 mutations.

METHODS: Cancer data was obtained from the Toronto FGICR from 1970 to 2007, including 353 persons with known mutations ( APC, CDH1, CRAC1, MLH1, MSH2, MSH6, MYH and FMS2), among

Canada were used to measure cancer risk in offspring of families with proven MSH2 and other mutations according to familial cancer status.

from the registry, 53 with bladder cancer (75%) and 24 UTCC (25%). 36 of these patients had a double primary cancer with 29 (41%) being colon cancer. Among patients with colon cancer, urothelial cancers appeared before colon cancer in 25% of cases. Within the 174 patients with proven MSH2 mutations, bladder cancer was found in 10 (5.74%) persons but none among the 179 patients with APC, CDH1, CRAC1,MLH1, MSH6, MYH or FMS2 mutations. There were 6 women and 4 men, in contrast with the expected male to female ratio for bladder cancer of 3:1 in Canada. This 5.74% risk for bladder cancer among MSH2 carriers is clearly increased as compared to the 2.5% and 0.5% lifetime risk among men and women in Canada, respectively. Regarding UTCC among MSH2 carriers, the observed risk was 2.9% (5/174) which

risk of upper tract TCC in these populations. CONCLUSIONS: Family members of HNPCC patients with

MSH2 mutations are at increased risk not only for upper UTCC as previously demonstrated (which actually can precede the diagnosis of colon cancer) but also of bladder cancer. None of the other genetic markers predisposing to HNPCC was involved in upper tract or bladder cancer TCC. Our study suggests that mutations of mismatch repair proteins may have an important contribution in the development of a subset of TCCs.

Source of Funding: None

754ASSOCIATION OF EGFR FAMILY POLYMORPHISMS AND BLADDER CANCER RISKA Karim Kader*, Lina Shao, Colin P Dinney, Yunfei Wang, Jian Gu, H Barton Grossman, Xifeng Wu. Winston Salem, NC, and Houston, TX.

INTRODUCTION AND OBJECTIVE: EGFR Family genes are expressed and over-expressed in many solid tumors including bladder. We tested the hypothesis that polymorphisms in these genes may alter bladder cancer risk.

METHODS: We examined the association of 4 polymorphisms in the EGFR, EGF and Her2 genes with bladder cancer risk in 580 bladder cancer patients and 580 controls matched to cases on age, gender, and smoking status. Further analyses were performed looking

RESULTS: The Her2 1200 GG genotype was associated with an overall 60% risk reduction for the development of bladder cancer

bladder cancer (OR 0.41 95%CI 0.21-0.80, p-0.008). The >16/>16 genotype of the EGFR microsatellite polymorphism was associated with

0.63 95%CI 0.43-0.94, p=0.023). CONCLUSIONS: The data show that the GG allele of the

with the >16/>16 genotype of the EGFR microsatellite. These results

may give insight into future potential therapeutic targets as well as the

Source of Funding: National Cancer Institute Public Health Service grants CA 74880.

755MODULATION OF CD44-EXPRESSING BLADDER CANCER CELLS BY HISTONE DEACETYLASE INHIBITORS: INCREASING THE EFFICACY OF CHEMO-RADIATION?Gary D Kao*, Melissa L Dowling, S Bruce Malkowicz. Philadelphia, PA.

INTRODUCTION AND OBJECTIVE: For patients with bladder cancer who are medically inoperable, chemo-radiation therapy may provide local control. Achieving maximal cancer cell killing and complete tumor eradication remain prime determinants of treatment success. Histone deacetylase-inhibitors (HDAC-I) comprise an intriguing class

enhance standard anticancer treatment. We investigated the effects on bladder cancer cell lines of HDAC-I’s when combined with chemo- and radiation therapy.

METHODS: Western blotting was performed to determine protein expression including ATM, phospho-ATM, CD44, PARP, caspase 3, and beta-actin as loading control. T24 and J82 human bladder cancer

(ADR)), and the HDAC-I’s trichostatin A (TSA) or valproic acid (VPA). Cell cycle distribution, viability and reproductive capability were determined

iodide exclusion and clonogenic survival assays. RESULTS: We discovered that exposure to either TSA or

VPA decreased expression of the putative stem cell marker CD44 in a time- and dose-dependent manner, an effect not seen with IR and ADR.IR and ADR individually resulted in modest cytotoxicity in the bladder cancer cells (e.g. percentage of nonviable T24 cells after IR was 14% and after ADR: 6%). In contrast, combined treatment with either HDACinhibitor substantially increased cell killing (e.g. the percentage nonviable cells: IR+TSA: 25%, ADR+TSA: 41%, IR+VPA: 23%, ADR+VPA: 49%. The combination of TSA or VPA also diminished activation of ATM and other components of the DNA damage repair pathway after exposure to the chemo-radiation, while also increasing caspase activation.

CONCLUSIONS: Combining the HDAC-Is with either IR or ADR led to considerably increased lethality in bladder cancer cells

cells was accompanied by down-modulation of the CD44 cancer stem cell marker, but also abrogation of the DNA damage response. These results suggest that HDAC-Is may be usefully incorporated with chemo-radiation therapy for targeting bladder cancer cells, with increased

mechanisms.Source of Funding: National Institutes of Health, National

Cancer Institute Grants RO1CA107956 and P01CA075138.

756ELEVATED TERE 1 PROTEIN INDUCES CYTOKINE EXPRESSION IN J82 BLADDER CANCER AND HUMAN IMMUNE CELLSWilliam J Fredericks*, Huiyi Wang, Yomgmu Zheng, Jean Boyer, Dan Schullery, Nicole Aqui, Priti Lal, John Tomaszewski, Terry McGarvey, S Bruce Malkowicz. Philadelphia, PA.

INTRODUCTION AND OBJECTIVE: The TERE 1 gene on chr. 1p36 encodes a 36.8 kDa. ER membrane protein with conserved expression in normal epithelial cells and immune cells. However, it is differentially reduced in T2 vs T1 transitional cell carcinoma (TCC). Forced TERE1 over-expression in the J82 TCC cell line inhibited soft