title: PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy.
abstract: When distinguishing between indolent and potentially harmful prostate cancers, the Gleason score is the most important variable, but may be inaccurate in biopsies due to tumor under-sampling. This study investigated whether a molecular feature, PTEN protein loss, could help identify which Gleason score 6 tumors on biopsy are likely to be upgraded at radical prostatectomy. Seventy one patients with Gleason score 6 tumors on biopsy upgraded to Gleason score 7 or higher at prostatectomy (cases) were compared with 103 patients with Gleason score 6 on both biopsy and prostatectomy (controls). A validated immunohistochemical assay for PTEN was performed, followed by fluorescence in situ hybridization (FISH) to detect PTEN gene deletion in a subset. PTEN protein loss and clinical-pathologic variables were assessed by logistic regression. Upgraded patients were older than controls (61.8 vs 59.3 years), had higher pre-operative PSA levels (6.5 vs 5.3 ng/ml) and a higher fraction of involved cores (0.42 vs 0.36). PTEN loss by immunohistochemistry was found in 18% (13/71) of upgraded cases compared with 7% (7/103) of controls (P=0.02). Comparison between PTEN immunohistochemistry and PTEN FISH showed the assays were highly concordant, with 97% (65/67) of evaluated biopsies with intact PTEN protein lacking PTEN gene deletion, and 81% (13/16) of the biopsies with PTEN protein loss showing homozygous PTEN gene deletion. Tumors with PTEN protein loss were more likely to be upgraded at radical prostatectomy than those without loss, even after adjusting for age, preoperative PSA, clinical stage and race (odds ratio=3.04 (1.08-8.55; P=0.035)). PTEN loss in Gleason score 6 biopsies identifies a subset of prostate tumors at increased risk of upgrading at radical prostatectomy. These data provide evidence that a genetic event can improve Gleason score accuracy and highlight a path toward the clinical use of molecular markers to augment pathologic grading.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine.|Department of Oncology, Johns Hopkins University School of Medicine.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lotan
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine.
authors.forename: Filipe Lf
authors.initials: FL
authors.lastname: Carvalho
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Peskoe
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Hicks
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Good
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine.
authors.forename: Helen
authors.initials: H
authors.lastname: Fedor
authors.affiliation: Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Humphreys
authors.affiliation: Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine.
authors.forename: Misop
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Platz
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.|Department of Pathology, University of Sao Paulo, Ribeirão Preto, Brazil.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine.|Department of Oncology, Johns Hopkins University School of Medicine.|Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine.
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine.|Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.|Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine.
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
mesh_terms: D000368:Aged; D001706:Biopsy; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human