title: Next-generation repeat-free FISH probes for DNA amplification in glioblastoma in vivo: Improving patient selection to MDM2-targeted inhibitors.
abstract: A next-generation FISH probe mapping to the MDM2 locus-specific region has recently been designed. The level of MDM2 gene amplification (high versus low) may allow selection of patients for cancer treatment with MDM2 inhibitors and may predict their responsiveness. We investigated the spectrum of MDM2 gene alterations using the new probes in vivo after visualizing single neoplastic cells in situ from a series of glioblastomas. Signals from next-generation repeat-free FISH interphase probes were identified in tissue microarrays that included 3 spots for each of the 48 cases. The murine double minutes (MDM2)-specific DNA probe and the satellite enumeration probe for chromosome 12 were used. Three cases (6%) showed more than 25 signals (high gene amplification), and 7 (15%) showed 3-10 signals (gains); among these, 4 cases (8%) had an equal number of MDM2 and centromeric signals on chromosome 12 (polyploidy). Genomic heterogeneity was observed only in 3 cases with low gene amplification. In our series, 6% of glioblastomas exhibited high MDM2 amplification (in vivo) with a pattern related to the known double minutes/chromothripsis phenomenon (in situ), and only cases with low amplification showed genomic heterogeneity. We concluded that the rate of MDM2 gene amplification can be a useful predictive biomarker to improve patient selection.
authors.affiliation: Department of Diagnostics and Public Health, FISH Lab, AOUI Hospital Trust of Verona, Italy; Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy. Electronic address: matteo.brunelli@univr.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy.
authors.forename: Albino
authors.initials: A
authors.lastname: Eccher
authors.affiliation: Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cima
authors.affiliation: Anatomic Pathology, S. Chiara Hospital, Trento, Italy.
authors.forename: Tobia
authors.initials: T
authors.lastname: Trippini
authors.affiliation: Department of Diagnostics and Public Health, FISH Lab, AOUI Hospital Trust of Verona, Italy; Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pedron
authors.affiliation: Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chilosi
authors.affiliation: Anatomic Pathology, S. Chiara Hospital, Trento, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.affiliation: Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Department of Surgical Sciences, Neurosurgery Unit, AOUI Hospital Trust of Verona, Italy.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Pinna
authors.affiliation: Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cabrini
authors.affiliation: Oncology Unit, AOUI Hospital Trust of Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pilotto
authors.affiliation: Oncology Unit, AOUI Hospital Trust of Verona, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Carbognin
authors.affiliation: Oncology Unit, AOUI Hospital Trust of Verona, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.affiliation: Oncology Unit, AOUI Hospital Trust of Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Fioravanzo
authors.affiliation: Anatomic Pathology, Cazzavillan Hospital, Arzignano, Vicenza, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Schiavo
authors.affiliation: Department of Surgical Sciences, Neurosurgery Unit, AOUI Hospital Trust of Verona, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Meglio
authors.affiliation: Oncology, Camposampiero-Cittadella, ULSS15 Padova, Italy.
authors.forename: Teodoro
authors.initials: T
authors.lastname: Sava
authors.affiliation: Department of Surgical Sciences, Neurosurgery Unit, AOUI Hospital Trust of Verona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Belli
authors.affiliation: Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy; Anatomic Pathology, Pederzoli Hospital, Peschiera Del Garda, Verona, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Martignoni
authors.affiliation: Department of Diagnostics and Public Health, Anatomic Pathology, AOUI Hospital Trust of Verona, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ghimenton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015342:DNA Probes; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D015342:DNA Probes; D004273:DNA, Neoplasm; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Glioblastoma; MDM2 biomarker; gains; high amplification; next-generation FISH probes