The incidence of genetic PTEN alteration

The deletions involving the chromosome 10q, which hosts the PTEN locus, 10q23, in CaP is a frequently observed phenomenon. Modifications to PTEN in various stages of CaP have been characterized to include both homozygous and hemizygous deletions, as well as inactivating mutations. Although the incidence and the modes of these alterations have been inconsistent across studies, the severity of PTEN loss seems to correlate with disease progression [119]. Whereas locally confined CaP presents homozygous deletions of PTEN ranging from 0% to 15%, the incidence within metastases can increase up to 30%. Likewise, heterozygosity loss occurs in 13% of the locally confined cases and up to 39% in metastatic phenotypes [120]. Further support has comefrom interphase fluorescence in situ hybridization (FISH) analysis of histologic sections, which reported genomic deletion of PTEN in 23% of high-grade intraepithelial neoplasia (HGPIN) and 68% of prostate tumors [121]. Recently, Han et al., (2009) demonstrated that PTEN deletion occurs in 9% of premalignant prostate, a proportion which increases to 17% in localized CaP and to 54% when metastasized. Functional loss of PTEN can also be generated through point mutations, which are seen in upwards of 16% of primary tumor and 20% to 30% in advanced stages [120]. Taken together, these studies suggest the deletion of PTEN is likely a late genetic occurrence in CaP progression.

3.1.1. Mechanism of PTEN loss

Although the incidence PTEN alterations in CaP have been extensively characterized in the past ten years, the mechanism by which genomic PTEN deletions occur remains to be elucidated. The high frequency of large-scale chromosomal events leading to the loss of PTEN locus suggests unique features that may enhance DNA rearrangements at 10q23. Yoshimoto et al.,

(2012) identified recombination hotspots known as segmental duplications (SD) 17 and 18 to be located between PTEN and BMPR1A. The SDs are typically part of a 1-400 kB genomic region exhibiting over 90% homology [123, 124] responsible for improving the likelihood of constitutional microdeletion events [125]. Utilizing meta-analysis of published prostate cancer genomes to map 10q23 deletion sites and FISH for confirmation, Yoshimoto et al., (2012) demonstrates SD17-SD18 colocalizes with a deletion breakpoint hotspot occurring in 69% of PTEN losses, which suggests SD17 and SD18 facilitate homology-dependent rearrangements of DNA that lead to a PTEN deletion breakpoint. The presence of these SDs thus destabilizes the genome, predisposing CaP progenitors to genomic microdeletions that ultimately result in PTEN loss. Subsequent attenuated PTEN expression has been shown to further diminish genomic stability [126], leading to the acquirement of other chromosomal abnormalities [127]. Cells bearing homozygous PTEN deletion would have significant stronger growth advantage and predominate due a constitutively activation of the PI3K pathway. This sequence of events may explain the progressive loss of PTEN as prostate turmorigenesis continues.

3.1.2. The clinical and cellular impact of PTEN loss

The functional loss of PTEN in CaP has been shown by numerous studies to confer poor clinical prognosis and predict disease progression. Genomic PTEN deletions studied through either immunohistochemistry or FISH have been correlated with increased Akt phosphoryla-tion, higher Gleason grade, biochemical relapse, angiogenesis, and larger tumor sizes [123, 128-132]. Specifically, Yoshimoto et al., (2007) demonstrated that haploinsufficiency of PTEN is associated with an earlier onset of biochemical relapse after prostatectomy while bi-allelic deletion of PTEN is associated with an even shorter time to relapse. Additionally, loss of PTEN near the time of prostatectomy correlated strongly with extraprostatic extension and seminal vesicle invasion.

Decreased expression of PTEN profiled by high-density tissue microarray was shown to also increase the risk of tumor recurrence after radical prostatectomy [129]. Similar findings were reached in immunohistochemical evaluation of PTEN expression in CaP glands. Using a nested case-control study, the group Chaux et al., (2012) found patients with reduced PTEN expression was at a higher risk of relapse, independent of identified clinicopathological covariates. Their previous study also linked attenuated PTEN levels to faster onset of metastasis in CaP patients [134]. Additionally, the use of transgenic mouse models have served to recapitulate features of PTEN loss in humans and concomitantly fostered a greater understanding of the PI3K pathway alongside clinical studies. Prostate specific PTEN-/- null knockout mice proceeds linearly from acquiring prostatic intraepithelial neoplasia (PIN) to adenocarcinoma to metastasis, mimicking the disease progression in human CaP [135]. The prostate tumors also exhibited temporary regression following androgen ablation, but eventually proliferated androgen independently. Further, mice with one deactivated PTEN allele combined with p27KIP1 loss exhibit accelerated spontaneous neoplastic transformation and tumorigenesis [136]. These studies of mouse and human prostate cancers combine to emphasize haploinsuf-ficiency of PTEN as a key predictor of disease states in prostate cancer.

0 0

Post a comment