Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer.
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.
Institute of Pathology, Prostate Cancer Center and Section for Translational Prostate Cancer Research at the Clinic of Urology at University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Antje
A
Krohn
Tobias
T
Diedler
Lia
L
Burkhardt
Pascale-Sophie
PS
Mayer
Colin
C
De Silva
Marie
M
Meyer-Kornblum
Darja
D
Kötschau
Pierre
P
Tennstedt
Joseph
J
Huang
Clarissa
C
Gerhäuser
Malte
M
Mader
Stefan
S
Kurtz
Hüseyin
H
Sirma
Fred
F
Saad
Thomas
T
Steuber
Markus
M
Graefen
Christoph
C
Plass
Guido
G
Sauter
Ronald
R
Simon
Sarah
S
Minner
Thorsten
T
Schlomm
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D012008:Recurrence; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D014408:Biomarkers, Tumor; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017430:Prostate-Specific Antigen