Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer.
TMPRSS2:ERG fusions, in combination with deletion of the phosphatase and tensin homolog (PTEN) tumor suppressor, have been suggested to cooperatively drive tumor progression in prostate cancer. We utilized a novel heterogeneity tissue microarray containing samples from 10 different tumor blocks of 189 prostatectomy specimens to study heterogeneity of genomic PTEN alterations in individual foci. PTEN alterations were found in 48/123 (39%) analyzable individual tumor foci, including 40 foci with deletions, 7 with deletion and rearrangement, and 1 focus with rearrangement only. PTEN was homogeneously aberrant in only 4 (8%) and heterogeneously in 44 (92%) of the foci. We found a specific sequence of molecular events from PTEN breakage followed by deletion of DNA sequences flanking the breakpoint, resulting in homozygous deletion. The observation that 16 of 19 foci with homogeneous ERG positivity had focal PTEN alterations but none of 10 foci with PTEN alterations had focal ERG positivity (P<0.0001) suggests that PTEN alterations typically develop subsequent to ERG fusions. We demonstrate a high level of intratumoral heterogeneity of PTEN alterations with deletions and rearrangements that challenges potential PTEN routine diagnosis testing in biopsies. The observation that PTEN alterations develop subsequent to ERG fusion strongly suggests that ERG expression may directly drive development of PTEN aberrations.
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Antje
A
Krohn
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Fabian
F
Freudenthaler
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Silvia
S
Harasimowicz
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Martina
M
Kluth
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Sarah
S
Fuchs
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Lia
L
Burkhardt
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Phillip
P
Stahl
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Maria
M
C Tsourlakis
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Melanie
M
Bauer
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Pierre
P
Tennstedt
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Markus
M
Graefen
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Stefan
S
Steurer
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hueseyin
H
Sirma
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Guido
G
Sauter
1] Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Thorsten
T
Schlomm
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ronald
R
Simon
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Sarah
S
Minner
D000230:Adenocarcinoma / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human