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 BRCA1 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).


CONCLUSIONS
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.
Kolasa
I K
IK
Department of Molecular Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, Warsaw, Poland.
Rembiszewska
A
A
Janiec-Jankowska
A
A
Dansonka-Mieszkowska
A
A
Lewandowska
A M
AM
Konopka
B
B
Kupryjańczyk
J
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005260:Female; D019398:Genes, BRCA1; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics*
D009944:Organoplatinum Compounds; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human