CYP24A1 Is an Independent Prognostic Marker of Survival in Patients with Lung Adenocarcinoma

Purpose: The active form of vitamin D, 1 alpha,25-dihydroxyvitamin D-3 (1,25-D-3), exerts antiproliferative effects in cancers, including lung adenocarcinoma (AC). CYP24A1 is overexpressed in many cancers and encodes the enzyme that catabolizes 1,25-D-3. The purpose of our study was to assess CYP24A1 as a prognostic marker and to study its relevance to antiproliferative activity of 1,25-D-3 in lung AC cells. Experimental Design: Tumors and corresponding normal specimens from 86 patients with lung AC (stages I-III) were available. Affymetrix array data and subsequent confirmation by quantitative real time-PCR were used to determine CYP24A1 mRNA expression. A subsequent validation set of 101 lung AC was used to confirm CYP24A1 mRNA expression and its associations with clinical variables. The antiproliferative effects of 1,25-D-3 were examined using lung cancer cell lines with high as well as low expression of CYP24A1 mRNA. Results: CYP24A1 mRNA was elevated 8- to 50-fold in lung AC (compared to normal nonneoplastic lung) and significantly higher in poorly differentiated cancers. At 5 years of follow-up, the probability of survival was 42% (high CYP24A1, n = 29) versus 81% (low CYP24A1, n = 57) (P = 0.007). The validation set of 101 tumors showed that CYP24A1 was independently prognostic of survival (multivariate Cox model adjusted for age, gender, and stage, P = 0.001). A549 cells (high CYP24A1) were more resistant to antiproliferative effects of 1,25-D-3 compared with SKLU-1 cells (low CYP24A1). Conclusions: CYP24A1 overexpression is associated with poorer survival in lung AC. This may relate to abrogation of antiproliferative effects of 1,25-D-3 in high CYP24A1 expressing lung AC. Clin Cancer Res; 17(4); 817-26. (C) 2010 AACR.