Alterations in the RB1 pathway in low-grade diffuse gliomas lacking common genetic alterations

Young Ho Kim, Joel Lachuer, Michel Mittelbronn, Werner Paulus, Benjamin Brokinkel, Kathy Keyvani, Ulrich Sure, Karsten Wrede, Sumihito Nobusawa, Yoichi Nakazato, Yuko Tanaka, Anne Vital, Luigi Mariani, Hiroko Ohgaki*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)

Abstract

We recently reported that the vast majority (>90%) of low-grade diffuse gliomas (diffuse astrocytoma, oligoastrocytoma and oligodendroglioma) carry at least one of the following genetic alterations: IDH1/2 mutation, TP53 mutation or 1p/19q loss. Only 7% of cases were triple-negative (ie, lacking any of these alterations). In the present study, array comparative genomic hybridization (CGH) in 15 triple-negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 (p14 ARF, p15 INK4b, p16 INK4a loci) and 13q14-13q32 (containing the RB1 locus) in three and two cases, respectively. Further analyses in 31 triple-negative cases as well as a total of 160 non-triple-negative cases revealed that alterations in the RB1 pathway (homozygous deletion and promoter methylation of the p15 INK4b, p16 INK4a and RB1 genes) were significantly more frequent in triple-negative (26%) than in non-triple-negative cases (11%; P = 0.0371). Multivariate analysis after adjustment for age, histology and treatment showed that RB1 pathway alterations were significantly associated with unfavorable outcome for patients with low-grade diffuse glioma [hazard ratio, 3.024 (1.279-6.631); P = 0.0057]. These results suggest that a fraction of low-grade diffuse gliomas lacking common genetic alterations may develop through a distinct genetic pathway, which may include loss of cell-cycle control regulated by the RB1 pathway.

Original languageEnglish
Pages (from-to)645-651
Number of pages7
JournalBrain Pathology
Volume21
Issue number6
DOIs
Publication statusPublished - Nov 2011
Externally publishedYes

Keywords

  • IDH1
  • IDH2
  • RB1
  • TP53
  • diffuse glioma
  • p14
  • p15
  • p16

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