title: Single-cell genetic analysis reveals insights into clonal development of prostate cancers and indicates loss of PTEN as a marker of poor prognosis.
abstract: Gauging the risk of developing progressive disease is a major challenge in prostate cancer patient management. We used genetic markers to understand genomic alteration dynamics during disease progression. By using a novel, advanced, multicolor fluorescence in situ hybridization approach, we enumerated copy numbers of six genes previously identified by array comparative genomic hybridization to be involved in aggressive prostate cancer [TBL1XR1, CTTNBP2, MYC (alias c-myc), PTEN, MEN1, and PDGFB] in six nonrecurrent and seven recurrent radical prostatectomy cases. An ERG break-apart probe to detect TMPRSS2-ERG fusions was included. Subsequent hybridization of probe panels and cell relocation resulted in signal counts for all probes in each individual cell analyzed. Differences in the degree of chromosomal and genomic instability (ie, tumor heterogeneity) or the percentage of cells with TMPRSS2-ERG fusion between samples with or without progression were not observed. Tumors from patients that progressed had more chromosomal gains and losses, and showed a higher degree of selection for a predominant clonal pattern. PTEN loss was the most frequent aberration in progressers (57%), followed by TBL1XR1 gain (29%). MYC gain was observed in one progresser, which was the only lesion with an ERG gain, but no TMPRSS2-ERG fusion. According to our results, a probe set consisting of PTEN, MYC, and TBL1XR1 would detect progressers with 86% sensitivity and 100% specificity. This will be evaluated further in larger studies.
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Electronic address: heselmek@mail.nih.gov.
authors.forename: Kerstin M
authors.initials: KM
authors.lastname: Heselmeyer-Haddad
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Lissa Y
authors.initials: LY
authors.lastname: Berroa Garcia
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Amanda
authors.initials: A
authors.lastname: Bradley
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Leanora
authors.initials: L
authors.lastname: Hernandez
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Yue
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Campus University of Lübeck, Lübeck, Germany.
authors.forename: Jens K
authors.initials: JK
authors.lastname: Habermann
authors.affiliation: Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Campus University of Lübeck, Lübeck, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dumke
authors.affiliation: Institute of Pathology, University of Lübeck and University Medical Center Schleswig-Holstein, Campus University of Lübeck, Lübeck, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thorns
authors.affiliation: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Abbott Molecular, Des Plaines, Illinois.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Pestova
authors.affiliation: Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Burke
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh Ph.D. Program in Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania; Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania.
authors.forename: Salim A
authors.initials: SA
authors.lastname: Chowdhury
authors.affiliation: Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania; Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania.
authors.forename: Russell
authors.initials: R
authors.lastname: Schwartz
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, the National Institutes of Health, Bethesda, Maryland.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Paris
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011003:Ploidies; D011379:Prognosis; D011467:Prostate / Q000473:pathology; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D059010:Single-Cell Analysis
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human