Abstract
The phosphatase and tensin homolog gene (PTEN) on chromosome 10q23.3 is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen-independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in situ hybridization (FISH) assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, androgen receptor, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.
Highlights
Prostate cancer is one of the leading causes of cancer mortality in men in the Western world
Sircar et al [26] reported a positive correlation between phosphatase and tensin homolog gene (PTEN) deletion status and up-regulation of androgen receptor (AR) expression in Castration Resistant Prostate Cancer (CRPC) patients. These results suggest that AR expression levels differ according to the stage of the disease, with genomic amplification of AR likely to occur in CRPC, but rarely in untreated prostate cancer [43, 44]
Zhang et al [70] showed that inhibition of either mammalian target of rapamycin (mTOR) with ridaforolimus or Akt with MK2206 alone had no effect on the status of the other kinase in castrate-sensitive settings. Simultaneous inhibition of both mTOR and Akt demonstrated additive antitumor effects [70]. These findings strongly indicate that the mTOR signaling network in the PTEN-null tumor is independent of Akt activity and that both Akt and mTOR downstream signaling pathways play a part in PTEN-deficient prostate tumors
Summary
Reviewed by: Marco Alessandro Pierotti, Fondazione IRCCS IStituto Nazionale dei Tumori, Italy Angela Bononi, University of Hawaii, USA. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in situ hybridization (FISH) assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, androgen receptor, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are known to contribute to loss of PTEN function, and to prostate cancer initiation. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies
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