Relationship between PTEN Protein Loss and Microsatellite Instability in Endometrial Carcinoma
B Djordjevic, R Broaddus. M.D. Anderson Cancer Center, Houston, TX
Background: Mismatch repair (MMR) gene defects (especially MLH1, MSH2, and MSH6) are associated with microsatellite instability in endometrial carcinoma. Mutations in these genes occur in HNPCC, while MLH1 loss can also be found in sporadic tumors due to promoter methylation. PTEN is a lipid kinase tumor suppressor that negatively regulates the PI3K signaling pathway, which is an important driver of cell proliferation and survival. This pathway is implicated in the pathogenesis of endometrial carcinoma, with PTEN mutations occurring at high frequency. The aim of this study was to evaluate whether PTEN immunohistochemistry (IHC) could help identify endometrial cancers with microsatellite instability.
Design: IHC for PTEN and mismatch repair proteins (MLH1, MSH2 and MSH6) was performed in a cohort of 100 endometrioid and 54 non-endometrioid endometrial carcinoma cases. The patients, aged 28-92, had no known history of HNPCC. PTEN IHC was scored as positive (90% of tumor with diffuse cytoplasmic staining), negative (0% of tumor cells staining) and heterogeneous (distinct positive and negative foci). MMR IHC was scored as positive or negative. Adjacent normal tissue was used as an internal positive control.
Results: MMR loss was seen in 39 (25%) cases, of which 34 had MLH1 loss, 5 had MSH6 loss and 1 had combined MSH2/6 loss. PTEN was lost (negative and heterogeneous staining) more frequently in endometrioid tumors (75%) than their non-endometrioid counterparts (41%) (p=0.0001). A similar trend was observed with MMR IHC (31% and 17%, p=0.0569). In endometrioid carcinomas MMR loss occurred with a similar frequency in cases with PTEN loss (35%) compared to those without PTEN loss (20%) (p=0.216). However, in non-endometrioid tumors MMR loss was conspicuously absent in PTEN positive cases (3%) and appeared to be strongly associated with loss of PTEN (36%) (p=0.002).
Conclusions: For the first time, we report an interesting association of combined PTEN loss and microsatellite instability in non-endometrioid endometrial carcinomas. Therefore, positive PTEN IHC can be used to identify non-endometrioid endometrial cancer cases that do not require additional IHC for MLH1, MSH2, and MSH6.
Category: Gynecologic & Obstetrics
Monday, March 22, 2010 2:00 PM
Platform Session: Section C, Monday Afternoon