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

Conflict of interest statement: The authors do not declare any conflicts of interest. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. There is an urgent need for predictive progression markers to discriminate between aggressive and non-aggressive prostate cancers. By immunohistochemistry on a tissue microarray containing 12,427 prostate cancers, the authors demonstrate that strong cytoplasmic p62 staining was tightly linked to high Gleason grade, advanced pathological tumor stage, positive nodal status, positive resection margin, and early PSA recurrence. Analysis of cytoplasmic accumulation of p62 is a strong predictor of an adverse prognostic behavior of prostate cancer. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract 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 pathological tumor 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 presence of all tested deletions, including PTEN (p<0.0001), 6q15 (p<0.0001), 5q21 (p=0.0002), and 3p13 (p=0.0088), 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, irrespective 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 clinico-pathological findings. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.