Molecular analysis of endometrial pathogenesis in Lynch syndrome.

Abstract

5095 Background: Women with Lynch Syndrome (LS) have a 40-60% predicted lifetime risk of developing endometrial cancer (EC). We hypothesize that in LS-associated EC, normal endometrium accumulates molecular changes in a step-wise fashion similar to sporadic EC. The objective of this study was to investigate precursor lesions and identify molecular changes contributing to endometrial carcinogenesis in LS-associated EC. Methods: Women with a confirmed mismatch repair gene mutation for LS undergoing a prophylactic or therapeutic hysterectomy were eligible. Case controls were matched 2:1 for EC and hyperplasia based preferentially on age and histology. Molecular analysis of PIK3CA, KRAS, AKT, and CTNNB1 was performed using Sequenom MassArray system. PTEN expression was assessed by immunohistochemistry. Statistical analysis was performed using Fisher’s exact test. Results: There were 67 patients with LS (30 normal endometrium, 8 hyperplasia, 39 EC) and 84 patients (10 normal endometrium, 16 hyperplasia, 58 EC) in the case matched control group. Concurrent complex atypical hyperplasia (CAH) was found in EC in 11 (39.3%) and 21 (46.6%) of LS and sporadic cases respectively. Loss of PTEN expression did not differ between sporadic (69%) and LS EC (86.2%) (p=0.117). However, sporadic CAH demonstrated 68.8% PTEN loss compared to only 12.5% in LS CAH (p=0.056). There was no difference in KRAS frequency in sporadic EC (10.3%) compared to LS EC (3.4%) (p=0.416). PIK3CA mutations occurred more frequently in sporadic EC (39.7%) compared to LS EC (13.8%) (p=0.015). Sporadic EC (37.9%) had significantly more CTNNB1 mutations than LS EC (6.9%) (p= 0.002). There was no relationship between PIK3CA, KRAS, AKT and CTNNB1 mutation and loss of PTEN expression. Conclusions: Similar to sporadic EC, hyperplasia is part of the pre-invasive spectrum of disease in LS associated EC. While PTEN loss was common in both LS and sporadic EC, PIK3CA and CTNNB1 mutations were more frequent in sporadic EC than LS EC. Our results indicate that loss of PTEN expression is an early event in sporadic EC and that other common mutations in sporadic EC may have a lesser role in LS associated EC development.