ThePTENgene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletion


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Abstract

PTENis frequently inactivated during the development of many cancers, including prostate cancer, and both bi-allelic and mono-allelicPTENinactivation may contribute to tumorigenesis.PTENmutations in clinical cancer specimens can easily be recorded but mono- or bi-allelic gene deletions are often difficult to assess. We performed a comprehensive study to detectPTENinactivation in 40 locally progressive clinical prostate cancer specimens obtained by transurethral resection of the prostate, utilizing a variety of complementary technical approaches. The methods to detectPTENdeletion included allelotype analysis, dual-colour FISH and array-based CGH. We also applied a novel semi-quantitative approach, assessing thePTEN-WT(wild-type):PTEN-Ψ (pseudogene) ratio (WPR). Structural analysis ofPTENwas performed by single-strand conformational polymorphism (PCR-SSCP) and sequencing. PTEN protein expression was assessed by immunohistochemistry. Our data predict completePTENinactivation in 12 samples (30%), nine of these by bi-allelic deletion. Loss of onePTENcopy was also detected by several methodologies but the number could not be accurately assessed. Immunohistochemistry indicated the absence of PTEN protein in 15 samples, and heterogeneous expression of the protein in eight tumours. Taken together, these data show that bi-allelic deletion is a major mechanism ofPTENinactivation in locally progressive prostate cancer.

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