Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer

Antje Krohn, Tobias Diedler, Lia Burkhardt, Pascale Sophie Mayer, Colin De Silva, Marie Meyer-Kornblum, Darja Kötschau, Pierre Tennstedt, Joseph Huang, Clarissa Gerhäuser, Malte Mader, Stefan Kurtz, Hüseyin Sirma, Fred Saad, Thomas Steuber, Markus Graefen, Christoph Plass, Guido Sauter, Ronald Simon, Sarah MinnerThorsten Schlomm

Research output: Contribution to journalArticlepeer-review

238 Citations (Scopus)

Abstract

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene is often altered in prostate cancer. To determine the prevalence and clinical significance of the different mechanisms of PTEN inactivation, we analyzed PTEN deletions in TMAs containing 4699 hormone-naïve and 57 hormone-refractory prostate cancers using fluorescence in situ hybridization analysis. PTEN mutations and methylation were analyzed in subsets of 149 and 34 tumors, respectively. PTEN deletions were present in 20.2% (458/2266) of prostate cancers, including 8.1% heterozygous and 12.1% homozygous deletions, and were linked to advanced tumor stage (P < 0.0001), high Gleason grade (P < 0.0001), presence of lymph node metastasis (P = 0.0002), hormone-refractory disease (P < 0.0001), presence of ERG gene fusion (P < 0.0001), and nuclear p53 accumulation (P < 0.0001). PTEN deletions were also associated with early prostate-specific antigen recurrence in univariate (P < 0.0001) and multivariate (P = 0.0158) analyses. The prognostic impact of PTEN deletion was seen in both ERG fusion-positive and ERG fusion-negative tumors. PTEN mutations were found in 4 (12.9%) of 31 cancers with heterozygous PTEN deletions but in only 1 (2%) of 59 cancers without PTEN deletion (P = 0.027). Aberrant PTEN promoter methylation was not detected in 34 tumors. The results of this study demonstrate that biallelic PTEN inactivation, by either homozygous deletion or deletion of one allele and mutation of the other, occurs in most PTEN-defective cancers and characterizes a particularly aggressive subset of metastatic and hormone-refractory prostate cancers.

Original languageEnglish
Pages (from-to)401-412
Number of pages12
JournalAmerican Journal of Pathology
Volume181
Issue number2
DOIs
Publication statusPublished - 2012 Aug

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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