Despite the rising incidence of
clear cell renal cell carcinoma, the molecular events that support its development and progression remain unclear. Herein, we evaluate the association of
endothelin 2 expression with both
clear cell renal cell carcinoma development and progression-free survival. We conducted real-time polymerase chain reaction to determine
endothelin 2 expression levels on 238 patients who underwent
nephrectomy for localized
clear cell renal cell carcinoma, 161 of whom also had adjacent normal kidney samples available for analysis. To evaluate associations with
clear cell renal cell carcinoma development, linear mixed models were used to compare differential expression between
tumor and a normal kidney as well as to explore interactions with clinicopathologic features. To evaluate associations with prognosis, Cox proportional hazards models were used to assess the association of progression-free survival and
endothelin 2 expression in
tumor tissue. Overall,
endothelin 2 expression was higher in
tumor samples versus patient-matched normal kidney samples, with an average fold change of 1.99 (95% confidence interval, 1.48-2.60; P < .0001). This overexpression in
tumor versus normal kidney samples was more pronounced in low- compared with high-grade
tumors (interaction, P = .0002), in early- compared with late-stage
tumors (interaction, P = .001), and in
tumors without compared with those with
necrosis (interaction, P = .001). Moreover, an increasing
endothelin 2 expression in
tumors was associated with a longer progression-free survival (hazard ratio, 0.89; 95% confidence interval, 0.80-0.99; P = .03); however, after controlling for known clinicopathologic factors, this association was attenuated (hazard ratio, 0.99; 95% confidence interval, 0.89-1.09; P = .7). Up-regulation of
endothelin 2 is a common and early event in localized
clear cell renal cell carcinoma. Higher
tumor expression of
endothelin 2 is associated with a longer progression-free survival but not after adjustment for well-known pathologic indices. Thus, although
endothelin 2 does not appear to be an independent prognostic marker, there is evidence of a putative role in
clear cell renal cell carcinoma progression. If supportive mechanistic data can be produced,
endothelin 2 could represent a potential target for chemopreventive or neoadjuvant
therapeutics for
clear cell renal cell carcinoma.