Thursday, 5 March 2015

Identification and functional prediction of mitochondrial complex III and IV mutations associated with glioblastoma

http://neuro-oncology.oxfordjournals.org/content/early/2015/03/02/neuonc.nov020.long

Rhiannon E. Lloyd, Kathleen Keatley, D. Timothy J. Littlewood et al.

The role of mtDNA mutations in cancer is subtle. Across most cancers, it has been suggested that mutations are negatively selected for. In this study, the authors provide contrary evidence for glioblastoma multiforme (GBM). They searched for heteroplasmic mutations of complexes III and IV from a mixture of cell lines and human biopsies in GBM patients. They clustered mutations according to three parameters: prevalence in the GBM population; prevalence in the general population; and heteroplasmy level, using ANOVA to check statistical significance. This split the >200 identified mutations into a group of 9 rare functional GBM mutations, and nonfunctional mutations. 43% of GBM tumours carried at least one of the functional mutations.

They mapped the mutations onto bovine crystal structures of the corresponding enzymes, to classify each mutation into one of the following groups: i) frameshift, ii) active site, iii) binding pocket, iv) protein interaction region, v) non-functional. 3D modelling provided mechanistic insight into the function of these mutations.


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