title: Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4.
abstract: Purpose:The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established.Experimental Design:Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities.Results:Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci.Conclusions:These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention.Clin Cancer Res; 23(14); 3823-33. ©2017 AACR.
authors.affiliation: Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.|Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Sowalsky
authors.affiliation: Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.|Winship Cancer Institute, Department of Urology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Haydn T
authors.initials: HT
authors.lastname: Kissick
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Gerrin
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Schaefer
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Russo
authors.affiliation: Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: M Simo
authors.initials: MS
authors.lastname: Arredouani
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Bubley
authors.affiliation: Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.|Winship Cancer Institute, Department of Urology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Sanda
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. sbalk@bidmc.harvard.edu hye@bidmc.harvard.edu.
authors.forename: Huihui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. sbalk@bidmc.harvard.edu hye@bidmc.harvard.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53