CHROMOSOME 9P DELETIONS IN CLEAR CELL RENAL CELL CARCINOMA ARE ASSOCIATED WITH AGGRESSIVE DISEASE

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THE JOURNAL OF UROLOGY®

distinguish two distinct ccRCC subtypes, termed A and B, which could be differentiated with as few as 44 mRNA probes. To validate these results, the 44-probe set was applied to an independent set of tumors on a different array platform. Clinical characteristics and outcomes of tumor subtypes A and B were examined. RESULTS: Clustering of two distinct subtypes of ccRCC was refined to a 44-probe set that was then validated on an independent set of 177 clear cell tumors. Examination of the clinical characteristics of the tumors showed that the patients in both groups were similar in terms of age, gender, stage, and pathologic characteristics, but the two clusters demonstrated a survival benefit for Cluster A compared to Cluster B with a high degree of statistical significance. CONCLUSIONS: This study has identified a simple, reliable and robust means to genetically define ccRCC subtypes with potential to impact prognosis of overall survival. The establishment of this expression signature has the potential to be a tremendous aid in clinical prognostication in ccRCC. Source of Funding: NIH

306 CHROMOSOME 9P DELETIONS IN CLEAR CELL RENAL CELL CARCINOMA ARE ASSOCIATED WITH AGGRESSIVE DISEASE. Jeffrey C La Rochelle*, Aditi Dastane, Nagesh Rao, Tobias Klatte, Brian Shuch, Michela de Martino, Nazy Zomorodian, Fairooz Kabbinavar, Jonathan W Said, Arie S Belldegrun, Allan J Pantuck, Los Angeles, CA INTRODUCTION AND OBJECTIVE: Identifying markers of adverse prognosis is useful in predicting recurrence and will help select patients for additional treatment when effective adjuvant treatements are developed. We investigated whether deletion of chromosome 9p in clear cell renal cell carcinoma (ccRCC) predicts worse disease-specific (DSS) and recurrence-free survival (RFS). METHODS: 316 patients undergoing nephrectomy prior to 2001 were included in a previously constructed tissue microarray (TMA). 9p deletions were detected in these tumors by fluorescent in situ hybridization using a commercially available probe (LSI p16/CEP 9 Dual Color Probe; Vysis, Downers Grove, IL). An additional 389 patients undergoing nephrectomy after 2001 had cytogenetics peformed on fresh tissue retrieved at the time of surgery. Clinical data was recorded, including tumor grade, stage, size, 9p deletion status, nodal involvement, and the presence of metastasis. Disease-specific survival was determined for all patients, and recurrence-free survival was determined for patients with localized disease (N0M0). Outcomes were stratified by 9p deletion status, and a Cox proportional hazards model was constructed using TNM staging, size, grade, and 9p status. For localized disease, the model contained T stage, size, grade, and 9p status. RESULTS: 9p deletions were detected in 97 tumors (14%). Fifty-four percent of 9p-deleted tumors were high grade (G3-4) vs. 38% without 9p deletions (p<0.01). Sixty percent of 9p-deleted tumors were T3-4 vs, 38% without 9p deletions (p<0.01). Fifty-five percent of those with 9p deletions had positive nodes or distant metastases vs. 34% of those without 9p deletions (P<0.01). Median DSS for those with and without 9p deletions was 80 months and 37 months, respectively (p<0.01). 9p deletion status did not have an independent effect on DSS in the overall group (HR 1.2, p=0.18). In localized disease, median RFS for those with 9p deletions was 53 months and was not reached in those without 9p deletions (p<0.01). An independent effect on RFS was seen for 9p deletions in this group (HR 2.3, p<0.01). CONCLUSIONS: Deletion of chromosome 9p in ccRCC is not infrequent and is associated with higher grade, higher T stage, and nodal or distant disease. 9p deletion also independently confers a worse prognosis in localized ccRCC. Identifying patients with 9p deletions allows better risk stratification for surveillance protocols, and eventually for adjuvant trials. Genes on chromosome 9p may be involved with progression of ccRCC. Source of Funding: Novartis

Vol. 181, No. 4, Supplement, Sunday, April 26, 2009

307 EXPRESSION OF AMIDATED AND NON-AMIDATED PEPTIDES DERIVED FROM PROGASTRIN-RELEASING PEPTIDE IN RENAL CANCERS, AND RENAL CANCER CELL LINES. Joseph Ischia, Damien M Bolton*, Liesl Ischia, Oneel Patel, Rachele Lockie, Graham Baldwin, Arthur S Schulkes, Melbourne, Australia INTRODUCTION AND OBJECTIVE: Tyrosine kinase inhibitors are standard of treatment for advanced renal cell cancer however resistance regularly ensues. Other growth factors potentially stimulating renal cancer include gastrin-releasing peptide (GRP, a 10 amino acid peptide processed from a 125 amino acid prohormone, proGRP, which plays a role in metabolism, organ development and behaviour. Importantly, it has been recognised as a potent mitogen in many tumours including small cell lung, pancreatic, breast and prostate cancer. Amidated GRP (GRP18-27) was thought to be the only biologically active product of proGRP, but it has been shown that fragments from the C-terminal of proGRP are biologically active and may be the predominant form in tumour tissues. While preliminary evidence has linked GRP to renal tumorigenesis, little is known about the expression of the different forms proGRP derived peptides in renal cancer. METHODS: Seven human renal cancer cell lines (ACHN, Caki-1, Caki-2, SKRC-01, SKRC-09, SKRC-17, and SKRC-52) were investigated for their expression of binding sites for amidated GRP18-27 (termed GRP) and two non-amidated fragments from proGRP: proGRP47-68 and proGRP80-97. Immunohistochemistry, radioimmunoassay, and ELISA were used to determine the relative expression of amidated and non-amidated proGRP derived peptides in ACHN, Caki-1, and Caki-2 renal cancer cell lines and in resected human renal cancers. RESULTS: GRP binding sites were found on all cell lines except Caki-1. The level of bound radioactivity ranged from 69cpm/106 cells for SKRC-17 to 885cpm/106 cells for SKRC-52. GRP receptor expression was detected in the same cell lines using immunohistochemistry. Five of the seven cell lines had binding sites for proGRP47-68 or proGRP80-97. Using immunohistochemistry, GRP, proGRP, and GRP receptor were expressed in most renal cancers although expression was often heterogenous within a tumour. RIA and ELISA revealed that ACHN, Caki-1 and Caki-2 cell lines contain non-amidated proGRP fragments but not the fully processed amidated GRP18-27. CONCLUSIONS: Non-amidated proGRP is present in renal cancers and renal cancer cell lines, but not always the fully processed amidated GRP. Receptors for GRP and proGRP are expressed on most renal cancer cell lines and certain renal cancer phenotypes. As GRP and proGRP are known stimulants of cellular proliferation and migration, it is feasible that these peptides are involved in the continuing progression of renal cancers. Source of Funding: Royal Australasian College of Surgeons

308 HEPATITIS C AS A RISK FACTOR FOR RENAL CELL CARCINOMA Craig G Rogers*, Manish N Patel, Lois Lamerato, Stuart Gordon, Detroit, MI INTRODUCTION AND OBJECTIVE: Chronic hepatitis C virus (HCV) is associated with liver and lymphoproliferative diseases as well as chronic kidney disease. We observed a higher than expected prevalence of HCV infection among patients with renal cell carcinoma (RCC) by examining our health system cancer registry. We found that 33/765 (4.3%) consecutive RCC cases diagnosed between 1997 and 2007 were HCV seropositive. We therefore sought to determine whether HCV confers an increased risk for the development of RCC. METHODS: We used administrative data from a large integrated health care system to explore the incidence of RCC among HCV infected persons. Adults testing anti-HCV positive (HCV +) between 1997 and 2006 were compared to a control cohort testing anti-HCV negative (HCV) during the same time period; HBsAg and HIV positive patients were excluded. Data from the system’s registry identified all RCC patients