title: Clinical stratification of glioblastoma based on alterations in retinoblastoma tumor suppressor protein (RB1) and association with the proneural subtype.
abstract: A recent study of CDK4/6 inhibitors in glioblastoma (GBM) xenografts identified retinoblastoma tumor suppressor protein RB1 status as a determinant of tumor therapeutic efficacy. Because of the need for clinically applicable RB1 testing, we assessed the utility of 2 complementary methods for determining RB1 status in GBM. Using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), we analyzed 34 GBMs that had also undergone molecular characterization as part of The Cancer Genome Atlas (TCGA). By IHC, 4 tumors (11.8%) had complete loss of RB protein expression, including 2 with homozygous deletion of RB1 by FISH and 1 with hemizygous deletion of RB1 by FISH combined with a novel nonsense mutation in RB1. Consistent with these results, in an independent set of 51 GBMs tested by IHC, we demonstrated loss of RB1 protein in 5 (9.8%). In GBM molecular subtype analysis of TCGA data, complete loss of RB1 transcript expression was seen in 18 (10.6%) of 170 tumors, and these were highly enriched for, but not exclusive to, the proneural subtype (p < 0.01). These data support the use of IHC for determining RB1 status in clinical GBM specimens and suggest that RB1 alterations may be more common in certain GBM subgroups.
authors.affiliation: Division of Neuropathology, Department of Pathology, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Goldhoff
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clarke
authors.forename: Ivan
authors.initials: I
authors.lastname: Smirnov
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D056726:Genetic Association Studies / Q000379:methods; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009474:Neurons / Q000473:pathology; D012175:Retinoblastoma / Q000235:genetics* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics*; D013234:Stem Cells / Q000473:pathology
chemical_list: D016160:Retinoblastoma Protein