Analysis of Molecular Targets for Renal Cell Carcinoma
Jennifer Prather, Snehal Sonawane, Grace Chappell, Sanjeev Akkina, Valerie Lindgren, Suman Setty. University of Illinois at Chicago, Chicago, IL
Background: Increased interest has developed in elucidating the molecular processes surrounding development of renal cell carcinomas. Decreased activity of the PTEN tumor suppressor gene, which functions by antagonizing PI3K/AKT/mTOR signaling, has been implicated in tumorigenesis of clear cell renal cell carcinoma (ccRCC). The methods by which PTEN is downregulated include gene loss and aberrant phosphorylation and acetylation. Recent studies focus on the use of immunohistochemistry (IHC) to evaluate PTEN status. However, the clinical significance of IHC evaluation has yet to be proven. Determination of affected pathways in ccRCC may be important to both predict outcome and choose effective treatments, such as mTOR inhibitors, for ccRCC patients. As appropriate identification of the significant molecular characteristics of ccRCC tumors is essential, we sought to identify the relationship of PTEN IHC and fluorescence in situ hybridization (FISH) with Fuhrman grade and survival.
Design: We have constructed a tissue microarray of 139 primary RCCs including 104 ccRCCs which were characterized using light microscopy and IHC. We performed IHC (n=102) and FISH (n=34) with the Abbott Molecular PTEN probe with centromeric repeat sequences as control to identify loss of PTEN. Cells with 20% or greater deletion of PTEN or monosomy of chromosome 10 were considered positive. The results were analyzed in comparison to Fuhrman grade and survival.
Results: Our study set demonstrated a correlation of Fuhrman grade with survival (p=<0.0001), a well known observation in the literature. Our population included 38% Caucasian, 33% African American, 23% Hispanic patients with 53% women. All Fuhrman grades were represented with 13% of cases grade 1, 49% grade 2, 27% grade 3 and 11% grade 4 tumors. Reduced PTEN IHC staining did not demonstrate any correlation with outcome (p=0.15, ns) or Fuhrman grade (p=0.71, ns). PTEN FISH showed deletion of 10q23 or monosomy 10 in 14/34 cases (no correlation with outcome (p=0.80, ns) or Fuhrman grade (p=0.23, ns)). 42% of cases with loss and only 30% of the non-loss cases were of higher Fuhrman grade (grade 3 and 4) (p=0.24, ns). Additionally, the cases with decreased IHC staining did not correlate with the cases demonstrating genetic loss.
Conclusions: In our study, PTEN IHC did not demonstrate significant associations with higher nuclear grade or poor outcome, supporting the recent hypothesis that loss of PTEN occurs early in the course of ccRCC development. However, our results suggest that FISH for loss of PTEN may be a method to identify a subset of tumors with poor outcome.
Monday, March 19, 2012 1:00 PM
Poster Session II # 287, Monday Afternoon