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  • 1
    Keywords: EXPRESSION ; GENE ; PROTEIN ; HIGH-RISK ; POOR-PROGNOSIS ; AKT ; IMMUNOHISTOCHEMICAL DETECTION ; PTEN/MMAC1 ; SUPPRESSOR ; FISH ANALYSIS
    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-naive 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.
    Type of Publication: Journal article published
    PubMed ID: 22705054
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  • 2
    Keywords: PATHWAYS ; BREAST-CANCER ; PROGRESSION ; SIGNAL-TRANSDUCTION ; TUMOR-SUPPRESSOR GENE ; PTEN ; MAPK ; TUMORIGENESIS ; BETA-ACTIVATED KINASE-1 ; TAK1
    Abstract: 6q12-22 is the second most commonly deleted genomic region in prostate cancer. Mapping studies have described a minimally deleted area at 6q15, containing MAP3K7/TAK1, which was recently shown to have tumor suppressive properties. To determine prevalence and clinical significance of MAP3K7 alterations in prostate cancer, a tissue microarray containing 4699 prostate cancer samples was analyzed by fluorescence in situ hybridization. Heterozygous MAP3K7 deletions were found in 18.48% of 2289 interpretable prostate cancers. MAP3K7 deletions were significantly associated with advanced tumor stage (P〈0.0001), high Gleason grade (P〈0.0001), lymph node metastasis (P〈0.0108) and early biochemical recurrence (P〈0.0001). MAP3K7 alterations were typically limited to the loss of one allele as homozygous deletions were virtually absent and sequencing analyses revealed no evidence for MAP3K7 mutations in 15 deleted and in 14 non-deleted cancers. There was a striking inverse association of MAP3K7 deletions and TMPRSS2:ERG fusion status with 26.7% 6q deletions in 1125 ERG-negative and 11.1% 6q deletions in 1198 ERG-positive cancers (P〈0.0001). However, the strong prognostic role of 6q deletions was retained in both ERG-positive and ERG-negative cancers (P〈0.0001 each). In summary, our study identifies MAP3K7 deletion as a prominent feature in ERG-negative prostate cancer with strong association to tumor aggressiveness. MAP3K7 alterations are typically limited to one allele of the gene. Together with the demonstrated tumor suppressive function in cell line experiments and lacking evidence for inactivation through hypermethylation, these results indicate MAP3K7 as a gene for which haploinsufficency is substantially tumorigenic.
    Type of Publication: Journal article published
    PubMed ID: 23370768
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