CASP9 germline mutation in a family with multiple brain tumors

Michael W. Ronellenfitsch, Ji Eun Oh, Kaishi Satomi, Koichiro Sumi, Patrick N. Harter, Joachim P. Steinbach, Jörg Felsberg, David Capper, Catherine Voegele, Geoffroy Durand, James McKay, Florence Le Calvez-Kelm, Jens Schittenhelm, Barbara Klink, Michel Mittelbronn*, Hiroko Ohgaki

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)


We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which three brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li–Fraumeni-like syndrome. Whole exome sequencing revealed a germline stop-gain mutation (R65X) in the CASP9 gene, which encodes caspase-9, a key molecule for the p53-dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase-9 immunohistochemistry showed the absence of caspase-9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li–Fraumeni-like family lacking a TP53 germline mutation.

Original languageEnglish
Pages (from-to)94-102
Number of pages9
JournalBrain Pathology
Issue number1
Publication statusPublished - Jan 2018
Externally publishedYes


  • CASP9
  • Li–Fraumeni-like syndrome
  • astrocytoma
  • exome sequencing


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