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Non-Mendalian inheritance of extrachromosal DNA elements can drive disease evolution in glioblastoma

Genomic heterogeneity of glioblastoma (GBM) is suspected to contribute to the poor response to therapy of this disease. We compared molecular characteristics between primary GBM, neurospheres and orthotopic xenograft models derived from the same parental tumor. Driver alterations were in majority propagated from tumor to model systems. Extrachromosomal amplifications of MET, a proto-oncogene coding for a receptor tyrosine kinase, were detected in three primary GBM, largely discarded in neurospheres cultures, but resurfaced in xenografts. The clonal dynamics inferred by somatic single nucleotide variants (sSNVs) in MET-amplified samples diverged from the pattern delineated by the MET amplification event suggesting that the MET event and sSNVs were inherited in different manners. Our analysis shows that extrachromosomal elements are able to drive tumor progression.

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Dataset ID Description Technology Samples
EGAD00001002214 Illumina HiSeq 2000 64
EGAD00001002219 Illumina HiSeq 2000 82
EGAD00001002245 Illumina HiSeq 2000 82
EGAD00001002264 PacBio RS II 2
Publications Citations
Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma.
Nat Genet 50: 2018 708-717
155
Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription.
Cancer Cell 39: 2021 694-707.e7
101
Unscrambling cancer genomes via integrated analysis of structural variation and copy number.
Cell Genom 2: 2022 100112
39