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Friday Science Review: February 3, 2012

Pathogenesis of Paediatric Glioblastoma Multiforme

McGill University ♦ Genome Quebec Innovation Centre

Published in Nature, January 29, 2012

Researchers have not only discovered the first recurring mutation in a human histone but have uncovered a key pathway involved in the formation of paediatric glioblastoma multiforme (GBM). This highly aggressive form of cancer is almost always lethal. Previously acquired gene expression patterns suggest that the mechanisms underlying GBM formation in children and adults are different. Mutations involved in the pathogenesis of GBM were identified by sequencing the exomes of 48 paediatric GBM samples. A chromatin remodelling pathway involving the histone H3.3 and the genes ATRX and DAXX seems to be at the heart of transformation. Researchers found that mutations in H3F3A, the gene encoding H3.3, lead to amino acid substitutions in the histone tail, a portion responsible for key regulatory post-translational modifications. In addition, mutations in ATRX and DAXX, both part of a chromatin remodelling complex that incorporates H3.3 histones at telomeres, were also identified in many of the patient samples. Subsequent screening of a large cohort (n=748) of gliomas showed that H3F3A mutation is frequently found in GBM and is highly specific to children.

The mutations identified in this study were associated with elongated telomeres. During the normal aging process telomeres shorten over time, and in a sense are a ‘biological clock’ that dictates the length of a cell’s life. Eventually, after many cell divisions, telomeres reach a critically short length and the cell undergoes senescence and/or programmed cell death. This is one mechanism by which the human body has evolved to prevent cells from accruing enough genomic mutations to undergo malignant transformation. Telomere elongation allows cells to live beyond their normal biological lifespan. Cells with elongated telomeres become dangerous as they are allowed to continue to live in the presence of mutational ‘build up’. Upregulation of the enzyme telomerase, which helps maintain telomere length through the addition of DNA to the ends of chromosomes, is also associated with cellular immortalization.

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