Purpose: Despite incidence rates that have been rising for decades, the molecular underpinnings that support the development of clear cell renal cell carcinoma (ccRCC) remain unclear. Herein, we evaluate expression levels of the hypoxia-induced autocrine survival factor endothelin-2 (EDN2) in patient-matched ccRCC and normal kidney samples. Methods: We identified 169 patients who underwent nephrectomy for histologically confirmed, localized ccRCC at our institution from 2000 to 2003 and had

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... h-frozen tumor and normal kidney samples available. After mRNA was extracted from microdissected tissue, we conducted real time PCR to determine expression levels of EDN2. We normalized the expression data using four control genes and then fit linear mixed models to evaluate differential expression between tumor and normal samples. In addition, we explored potential interactions with relevant clinicopathologic characteristics including tumor stage and grade. Results: Of the 161 patients analyzed, 65% were male, 58% were stage pT1, and 43% were nuclear grade 1 or 2. Overall, EDN2 expression was higher in tumor samples compared to paired normal samples with an average fold change (FC) of 2.0 (P-value < 0.0001). This overexpression in tumor versus normal tissue was apparent in early stage (pT1) tumors but not later stage (pT2, pT3) tumors (FC of 2.9 v. 1.1 respectively; interaction P-value = 0.001). Similarly, over-expression was more pronounced in low grade (1, 2) tumors compared to high grade (3, 4) tumors (FC of 3.5 v. 1.3 respectively; interaction P-value = 0.0002). Conclusions: While independent validation is required, our patient-based data suggest that up-regulation of EDN2 is a common and early event in localized ccRCC. If confirmed in future studies, EDN2 could represent a target for the development of novel chemopreventive or neo-adjuvant therapeutics for ccRCC. Circulating 25-Hydroxyvitamin-D and Risk of Colorectal Adenomas and Hyperplastic Polyps Adams S, Newcomb P, Burnett-Hartman A, Mandelson M, Potter J Background: Colorectal adenomas are clear precursors of cancer; hyperplastic polyps have recently been hypothesized to also have malignant potential. However, these two distinct colorectal lesions are probably on different molecular pathways to neoplasia. An inverse association between vitamin D and adenoma risk has been reported, but this is the first study, to our knowledge, that examines circulating 25(OH)D in relation to risk of hyperplastic polyps. Methods: We conducted a colonoscopy-based casecontrol study of adenomas and hyperplastic polyps among 474 members of a large integrated health plan. Self-administered questionnaires provided data on demographics and colorectal polyp risk factors, and we assayed plasma samples donated by participants at the time of the colonoscopy for total 25-hydroxyvitamin-D (25(OH)D) concentration. Polytomous regression was used to estimate separate odds ratios for adenomas (n = 153) and hyperplastic polyps (n = 91) by tertile of 25(OH)D. Results: An inverse association between 25(OH)D and adenomas was observed (comparing upper to lower tertiles: adjusted OR [95%CI]: 0.60 [0.34-1.08]). After restriction of the analyses to study participants with no history of polyps, this OR estimate moved further from the null and became statistically significant (adjusted OR [95% CI]: 0.43 [0.20-0.96]). In comparison, no statistically significant association between hyperplastic polyps and 25(OH)D was observed among the full study participants (adjusted OR [95%CI]: 1.12 [0.59-2.13]) nor among those without prior polyps (adjusted OR [95%CI]: 1.27 [0.57-2.35]). Conclusions: There is no evidence in our study that the established inverse association between circulating 25(OH)D and colorectal adenoma applies to hyperplastic polyps.