Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer.
OBJECTIVE
Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells.


METHODS
To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, p62 protein levels were analyzed by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21, and 6q15 were available from earlier studies.


RESULTS
p62 immunostaining was absent in benign prostatic glands but present in 73% of 7,822 interpretable prostate cancers. Strong cytoplasmic p62 staining was tightly linked to high Gleason grade, advanced pathologic tumor (pT) stage, positive nodal status, positive resection margin, and early PSA recurrence (P < 0.0001 each). Increased levels of p62 were significantly linked to TMPRSS2-ERG fusions, both by FISH and immunohistochemical analysis (P < 0.0001 each). For example, moderate or strong p62 immunostaining was seen in 28.5% of cancers with TMPRSS2-ERG fusion detected by FISH and in 23.1% of cancers without such rearrangements (P < 0.0001). Strong p62 staining was significantly linked to the presence of all tested deletions, including PTEN (P < 0.0001), 6q15 (P < 0.0001), 5q21 (P = 0.0002), 3p13 (P = 0.0088), and 6q15 (P < 0.0001), suggesting a link between p62 accumulation and loss of genomic stability. The prognostic role of p62 protein accumulation was striking and independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA, regardless of whether preoperative or postoperative parameters were used for modeling.


CONCLUSIONS
Our study identifies cytoplasmic accumulation of p62 as a strong predictor of an adverse prognostic behavior of prostate cancer independently from established clinicopathologic findings.
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany. General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Germany.
Christoph
C
Burdelski
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Viktor
V
Reiswich
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Claudia
C
Hube-Magg
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Martina
M
Kluth
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Sarah
S
Minner
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Christina
C
Koop
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
Markus
M
Graefen
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
Hans
H
Heinzer
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Maria Christina
MC
Tsourlakis
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Corinna
C
Wittmer
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
Hartwig
H
Huland
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Ronald
R
Simon
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany. Department of Urology, Section for translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Germany.
Thorsten
T
Schlomm
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
Guido
G
Sauter
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany. s.steurer@uke.de.
Stefan
S
Steurer
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D000071456:Sequestosome-1 Protein; D046888:Tissue Array Analysis
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human