PTEN mutation, expression and LOH at its locus in ovarian carcinomas.: Relation to TP53, K-RAS and BRCA1 mutations

Objective. We aimed to evaluate frequency of PTEN mutation, LOH and expression in ovarian tumors. In search for a molecular pathway, we confronted PTEN gene mutations with TP53, K-RAS and BRCAl gene status in the same tumors. We also evaluated clinical significance of PTEN expression in a subgroup of patients uniformly treated with platinum-based regimens. Methods. Molecular analysis was performed on 105 ovarian tumors (100 carcinomas) with the use of the SSCP and sequencing. Seventy-six tumors were analyzed for LOH at 10q23 locus with the use of six polymorphic markers. Immunohistochemical PTEN expression was done on paraffin-embedded material. Multivariate and univariate analysis was performed with the STATA program. Results. PTEN mutations occurred in 5/100 (5%) of all carcinomas and in 3/15 (20%) of endometrioid carcinomas (EC). Low-grade EC that developed in borderline tumors had PTEN and/or K-RAS mutation (4/5, 80%), while high-grade EC had TP53 mutations only. There was a reverse association between PTEN and TP53 mutations (P = 0.005). LOH at PTEN locus was found in 60% of endometrioid and in 28% of serous and clear cell carcinomas. PTEN expression did not associate with PTEN mutations or LOH. Strong PTEN expression diminished risk of death in a TP53 positive group only (HR = 0.35, P = 0.029). Conclusion. Our results suggest that PTEN mutations may play a role in a development of low-grade endometrioid tumors. PTEN haploinsufficiency caused by LOH or epigenetic events may possibly contribute to development of other histological types and may be an adverse prognostic factor. (c) 2006 Elsevier Inc. All rights reserved.