Novel mutations target distinct subgroups of medulloblastoma

By G. Robinson, Matthew Parker, T. Kranenburg, Charles Lu, Xiang Chen, Li Ding, T. Phoenix, Erin K. Hedlund, Lei Wei, Xiaoyan Zhu and 40 more. Nature, 2012

834 citations recorded by the source corpus.

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6621113a3cebc3b49f339958a9dfb034e802037b

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Citations in the corpus

The whole-genome landscape of medulloblastoma subtypes (2017, neutral): “Re-analysis of NGS data derived from previous studies ( n = 173) 5,9,14 indicated that less than one-third of Group 3 (32”
Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma (2013, positive): “The somatic mutation rate in our series was markedly lower than those recently reported for the malignant pediatric brain tumor Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma medulloblastoma 10–12 and for several other pediatric solid tumors 13 .”
Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma (2014, positive): “The number of SVs and CNVs, background mutation rate, and number of nonsilent tier 1mutations were significantly higher in osteosarcoma compared with medulloblastoma and T-ALL (Robinson et al., 2012; Zhang et al., 2012; Figure 1B).”
Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition (2014, methodology): “Interestingly, mutations affecting the SWI-SNF complex, also mainly found in the WNT-MBs in children (Jones et al., 2012; Northcott et al., 2012a; Pugh et al., 2012; Robinson et al., 2012), were also frequently seen in adult SHH-MBs.”
Histone Modifications and Cancer. (2016, background): “More compelling evidence that accumulation of H3K27me3 is central to EZH2’s oncogenic effect in medulloblastoma is that EZH2 overexpression or amplification was found to be mutually exclusive to inactivating mutations in the reversing H3K27 demethylase UTX (KDM6A) (Robinson et al. 2012).”
Lessons from the cancer genome. (2013, neutral): “, 2012), and medulloblastoma (Robinson et al., 2012).”