Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

TY - JOUR

T1 - Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

AU - Burdelski, Christoph

AU - Reiswich, V.

AU - Hube-Magg, Claudia

AU - Kluth, Martina

AU - Minner, Sarah

AU - Koop, Christina

AU - Graefen, Markus

AU - Heinzer, Hans

AU - Tsourlakis, Maria Christina

AU - Wittmer, Corinna

AU - Huland, Hartwig

AU - Simon, Ronald

AU - Schlomm, Thorsten

AU - Sauter, Guido

AU - Steurer, Stefan

N1 - ©2015 American Association for Cancer Research.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - PURPOSE: Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells.EXPERIMENTAL DESIGN: 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.

AB - PURPOSE: Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells.EXPERIMENTAL DESIGN: 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.

U2 - 10.1158/1078-0432.CCR-14-0620

DO - 10.1158/1078-0432.CCR-14-0620

M3 - SCORING: Journal article

C2 - 25925890

VL - 21

SP - 3471

EP - 3479

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 15

ER -