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Peroxisome proliferator-activated receptor gamma (PPARG) gene amplifications in urothelial carcinoma (UC).

279 Background: PPARy is a steroid hormone receptor encoded by the PPARG gene (Chr 3p25). Data are conflicting regarding its role in UC. Some studies suggest activation has antiproliferative effects, and preclinical data indicate a potential role for PPARy agonists in cancer treatment. However, recent findings show that use of the PPARy agonist thiazolidinones (TZD) in type 2 diabetes is associated with increased risk of developing UC. To define the spectrum of PPARy aberrations in UC, DNA was evaluated to detect copy number gains/losses (CNG/CNL) of PPARG in three clinically annotated UC cohorts.


METHODS
Cohort A contained 97 patients with high-grade UC. Cohort B contained 94 patients with primary bladder tumors who developed metastatic UC. Cohort C had 33 patients with metastatic UC, including both primary and paired metastatic tissue for 14 patients. DNA from all tumors was subjected to copy number analysis (array comparative genomic hybridization for cohorts A and B and molecular inversion probe array for cohort C) to identify focal areas of CNG/CNL. Statistical analysis using RAE (cohort A) or GISTIC 2.0 (with CNG defined as log2 copy number ratio >0.8) in cohorts B/C was used to identify significant alterations.


RESULTS
The region containing PPARG showed CNG in 7%, 10%, and 15% of cohorts A, B and C, respectively. In cohort A, RAE p value was 5.36E-05 at the amplicon containing PPARG. In cohorts B and C GISTIC 2.0 q values were 9.75E-12 and 6.04E-10. PPARG CNG had no impact on survival in the cohorts with available survival data (A and B). Paired biopsies from primary and metastatic sites showed discordance in PPARG CNG in 2 cases. In 1 case CNG was present in the metastasis but not in the primary and in 1 case the opposite occurred.


CONCLUSIONS
PPARG shows significant CNGs in 7-15% of UC. Notably the RAF1 locus (a known oncogene) lies close to PPARG and could also represent the driver alteration within this amplicon. Investigation of the functional relevance of these CNGs is clearly warranted as it may be a driver of bladder cancer growth and progression. Determination of PPARG CNG status in UCs in a TZD treated population may provide mechanistic insights into the increased incidence of UC in patients treated with these agents.