106 THE JOURNAL OF UROLOGY® consists of four known members: ErbBI, ErbB2, ErbB3 and ErbB4. ErbBI/ErbB2 expression increases as PCa progresses to a hormome-refractory (HR) stage. ErbB3 expression is associated with patient mortality in early invasive ovarian cancer but little is known regarding its role in PCa progression.To determine whether ErbB3 could be used as a prognostic and/or diagnosis marker for PCa. METHODS: We studied the expression of ErbB3 in formalin-fixed, paraffin- embedded PCa specimens by immunohistochemistry. A tissue array containing 390 cores of radical prostatectomy-derived specimens of normal, hyperplasic, and PCa tissues from 81 patients was used. In addition, slides from 23 sections from patients having undergone radical prostactectomy and 20 sections obtained by transurethral resection of the prostate from hormone-resistant (HR) patients were also studied. RESULTS: In tissue array, ErbB3 positive staining (cytoplasmic and/or nuclear) was found in 90% of cores. Surprisingly, ErbB3, described as a cytoplasmic membrane protein, was localized in the nucleus of PC a tissues and the presence of the nuclear staining increased with Gleason grade. Nuclear staining was observed in 2143 (4.6%) normal tissues, 5125 (20%) PIN tissues, 641200 (32%) low Gleason grade (LGG) tissues, 741115 (64%) high Gleason grade (HGG) tissues, and in 6n (85%)of tissues from HR PCa. The ErbB3 nuclear localization can be used to differentiate normal prostate from PCa (P<O.OOI); and between tissues from non-hormono-refractory (NHR) versus HR PCa (P < 0.005). In the additonal tissue study, nuclear staining was also differentially observed in HR PCa (100%) compared to NHR PCa (65%). CONCLUSIONS: ErbB3 nuclear staining and/or intensity appears to associate with disease progression and the high frequency of ErbB3 nuclear localization in HR cores and HR tissue sections indicates that ErbB3 may also be useful as a potential prognosis marker for highly malignant PCa. Source of Funding: Prostate Cancer Research Fondation of Canada 387 WHOLE GENOME SCANNING IDENTIFIES GENOTYPES ASSOCIATED WITH RECURRENCE AND METASTASIS IN PROSTATE TUMORS Pamela L Paris*, Armann Andaya, Jane Fridlyand, Ajay Jain, Vivian Weinberg, David Kowbel, Jay Brebner, Jeff Simko, Stas Volik, Donna Albertson, Daniel Pinkel, San Francisco, CA; Phillip Febbo, Boston, MA ; Arul M Chinnaiyan, Kenneth Pienta, Ann Arbor, Ml; Mark A Rubin, Boston, MA; Peter R Carroll, San Francisco, CA; Herman van Dekken, Rotterdam, Netherlands Antilles; Colin Collins, San Francisco, CA INTRODUCTION AND OBJECTIVE: Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm among males in Western countries and is estimated to result in 28,900 deaths this year in the U.S. alone. The advent of widespread prostate specific antigen (PSA) screening has resulted in increased detection of prostate cancer at earlier stages. A persistent and recalcitrant problem is that men with pathologically similar tumors often exhibit markedly different clinical outcomes following surgery or radiation therapy, and metastasis is invariably fatal. It is imperative that new methods be developed for patient stratification based on risk of recurrence to enable appropriate patient management. METHODS: To address these issues, we analyzed prostate tumors using array comparative genomic hybridization (aCGH). The primary tumor cohort is from 64 patients, half of whom recurred postoperatively. Rising PSA following prostatectomy was used as a biochemical marker of disease recurrence. To extend this study, we included an independent set of 15 organ metastases in an exploratory exercise to determine whether BAC-based markers present in primary tumors might be predictive of occult metastasis or proclivity for metastasis. RNAs from a separate group of I 0 primary prostate tumors were used for expression studies. For the preliminary biomarker validation study, aCGH was performed on DNAs from an independent set of 27 primary prostate tumors. RESULTS: In the primary tumors, gain at llql3.1 was found to be predictive of postoperative recurrence independent of stage and grade. Expression results show MEN I at llql3.1 to be a candidate biomarker. Moreover, comparison with an independent set of metastases revealed 39 candidate markers associated with metastatic potential. In a preliminary study, the biomarker group alone could predict risk of recurrence with an accuracy of 81 %. CONCLUSIONS: Copy number aberrations at these loci may define metastatic genotypes. Patients identified as high risk of disease recurrence could be immediately treated with secondary therapies in an attempt to reduce or prevent recurrence. Source of Funding: UCSF Prostate Cancer SPORE, NIH Grant P50CA89520 *Presenting author. Vol. 173, No.4, Supplement, Sunday, May 22, 2005 388 SINGLE NUCLEOTIDE POLYMORPHISM (SNP) AND SPLICING VARIANT IN C-TERMINAL REGION OF TCF-4 GENE ARE RELATED TO THE PATHOGENESIS OF PROSTATE CANCER Hiroaki Shiina*, Izumo, Japan; Hideki Enokida, Shinji Urakami, Tatsuya Ogishima, Toshifumi Kawakami, Long-Cheng Li, San Francisco, CA; Hirofumi Kishi, Kazushi Shigeno, /zumo, Japan; Leopolda A Ribeiro-Filho, Alvaro S Sarkis, Siio Paulo, Brazil; Z Laura Tabatabai, Christopher J Kane, Peter R Carroll, San Francisco, CA; Mikio lgawa, Izumo, Japan; Rajvir Dahiya, San Francisco, CA INTRODUCTION AND OBJECTIVE: Transcriptional factor TCF-4 (human T-cell factor-4) and beta-catenin comprise the Wnt signal, which plays an important role in the malignant transformation process. TCF-4 splicing isoforms occur in the C-terminal region, where C-terminal binding protein (CtBP) sites are present and affect transcription. On the other hand, a TCF-4 isoform with exon 15 results in a short reading frame resulting in no CtBP. We hypothesize that single nucleotide polymorphism (SNP) in the C-terminnus of the TCF-4 gene (exon 17) and splicing forms with exon 15 are risk factors for pathogenesis of prostate cancer (PC). METHODS: To test our hypothesis, blood DNA samples from 187 PC and 95 benign prostatic hyperplasia (BPH) patients were analyzed for SNP in TCF-4. The genotype of the SNP of exon 17 (from CCC (Pro) or ACC (Thr)) was determined by sequence specific PCR and direct sequencing. Tissue RNA was extracted from 187 PC samples. In 129 PC patients, no additional therapy was performed before and after radical prostatectomy. Relative amounts of exon 15 (R-exon 15) were analyzed by quantitative RT-PCR using exon 3 ofTCF4 gene as internal reference. RESULTS: The prevalence of the genotype A/A was significantly lower in PC as compared to BPH. Patients with A allele had a decreased risk for PC, and the odds ratio for CIA and A/A was 0.30 (95% CI: 0.11-0.82) and 0.28 (95% CI: 0.10-0.75), respectively. The TCF-4 genotypes did not correlate with Gleason sum (GS) or pT category. With median follow-up of 33.4 months, the C/C genotype was likely to have lower PSA failure-free rate, when compared to the CIA or AlA genotype. The R-exon 15 was higher in GS ?:: 7 (3 .1 AU) than in GS :56 (1.9 AU). In addition, PC with higher R-exon 15 showed lower PSA failure-free rate than PC with lower R-exon 15. CONCLUSIONS: This is the first study showing that: (I) the A allele of exon 17 in the TCF-4 gene has a protective effect against PC and PSA failure and (2) PC cells with exon 15 are more likely to have an aggressive phenotype in relation to early PSA failure. Source of Funding: NIH grants (ROICA101844, ROIAG21418 , T32DK07790), VA Merit Review and REAP grants 389 CPG HYPERMETHYLATION OF ADENOMATOUS POLYPOSIS COLI (APC) PROMOTER IS A CANDIDATE BIOMARKER TO PREDICT BIOLOGICAL AGGRESSIVENESS OF LOCALIZED PROSTATE CANCER Hiroaki Shiina*, Izumo, Japan; Hideki Enokida, Shinji Urakami, Tatsuya Ogishima, Toshifumi Kawakami, Long-Cheng Li, San Francisco, CA; Hirofumi Kishi, Kazushi Shigeno, Izumo, Japan; Leopolda A Ribeiro-Filho, Alvaro S Sarkis, Siio Paulo, Brazil; Christopher J Kane, Peter R Carroll, San Francisco, CA; Mikio lgawa, /zumo, Japan; Rajvir Dahiya, San Francisco, CA INTRODUCTION AND OBJECTIVE: The adenomatous polyposis coli (APC) protein stabilizes beta-catenin and actively involves in the Wnt signaling pathway. The promoter of APC gene is frequently methylated in various cancers, however; the prevalence of APC methylation and its association with biological aggressiveness in prostate cancer (PC) remain unclear. We hypothesize that (I) promoter hypermethylation of APC gene contributes to the pathogenesis and progression of PC and (2) the hypermethylated APC promoter can identify PC patients that is likely to have early PSA failure after radical prostatectomy. METHODS: One hundred and eighty-two PC patients who underwent radical prostatectomy and 96 benign prostatic hyperplasia (BPH) patients who underwent transurethral resection of the prostate were used in this study. Tissue DNA was extracted after microdissection. The CpG hypermethylation of APC promoter was analyzed by methylation specific PCR and confirmed by DNA sequencing using bisulfite-modified DNA samples. RESULTS: The prevalence of APC methylation was significantly higher in PC samples compared to BPH samples (62.1% vs. 6.3%, respectively). Logistic regression analysis revealed that PC patients are 18.7 times more likely to have APC methylation than BPH patients (95% CI: 7.39-46.9). Stepwise increase of APC methylation was found along with increased Gleason sum (p= 0.0003) and pT category (p< O.OOOI). Likewise, APC methylation was significantly correlated with capsular penetration (p= 0.004), lymphatic vessel involvement (p= 0.012), venous involvement (p= 0.002) and perineural invasion (p = 0.047). On the other hand, among 129 PC patients that received no additional treatment before and after