title: PTEN loss and chromosome 8 alterations in Gleason grade 3 prostate cancer cores predicts the presence of un-sampled grade 4 tumor: implications for active surveillance.
abstract: Men who enter active surveillance because their biopsy exhibits only Gleason grade 3 (G3) frequently have higher grade tumor missed by biopsy. Thus, biomarkers are needed that, when measured on G3 tissue, can predict the presence of higher grade tumor in the whole prostate. We evaluated whether PTEN loss, chromosome 8q gain (MYC) and/or 8p loss (LPL) measured only on G3 cores is associated with un-sampled G4 tumor. A tissue microarray was constructed of prostatectomy tissue from patients whose prostates exhibited only Gleason score 3+3, only 3+4 or only 4+3 tumor (n=50 per group). Cores sampled only from areas of G3 were evaluated for PTEN loss by immunohistochemistry, and PTEN deletion, LPL/8p loss and MYC/8q gain by fluorescence in situ hybridization. Biomarker results were compared between Gleason score 6 vs 7 tumors using conditional logistic regression. PTEN protein loss, odds ratio=4.99, P=0.033; MYC/8q gain, odds ratio=5.36, P=0.010; and LPL/8p loss, odds ratio=3.96, P=0.003 were significantly more common in G3 cores derived from Gleason 7 vs Gleason 6 tumors. PTEN gene deletion was not statistically significant. Associations were stronger comparing Gleason 4+3 vs 6 than for Gleason 3+4 vs 6. MYC/8q gain, LPL/8p loss and PTEN protein loss measured in G3 tissue microarray cores strongly differentiate whether the core comes from a Gleason 6 or Gleason 7 tumor. If validated to predict upgrading from G3 biopsy to prostatectomy these biomarkers could reduce the likelihood of enrolling high-risk men and facilitate safe patient selection for active surveillance.
authors.affiliation: Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Trock
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Fedor
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Gurel
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Knudsen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, Los Angeles, CA, USA.
authors.forename: Samson W
authors.initials: SW
authors.lastname: Fine
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.affiliation: Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: H Ballentine
authors.initials: HB
authors.lastname: Carter
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lotan
authors.affiliation: Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Angelo M
authors.identifier: 0000-0003-4847-5307
authors.initials: AM
authors.lastname: De Marzo
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8; D006801:Humans; 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