Abstract
ABSTRACTWe previously reported the establishment of a rare xenograft derived from a recurrent oligodendroglioma with 1p/19q codeletion. Here, we analyzed in detail the exome sequencing datasets from the recurrent oligodendroglioma (WHO grade III, recurrent O2010) and the first-generation xenograft (xenograft1). Somatic SNVs and small InDels (n = 80) with potential effects at the protein level in recurrent O2010 included variants in IDH1 (NM_005896:c.395G>A; p. Arg132His), FUBP1 (NM_003902:c.1307_1310delTAGA; p.Ile436fs), and CIC (NM_015125:c.4421T>G; p.Val1474Gly). All but 2 of these 80 variants were also present in xenograft1, along with 7 new variants. Deep sequencing of the 87 SNVs and InDels in the original tumor (WHO grade III, primary O2005) and in a second-generation xenograft (xenograft2) revealed that only 11 variants, including IDH1 (NM_005896:c.395G>A; p. Arg132His), PSKH1 (NM_006742.2:c.650G>A; p.Arg217Gln), and SNX12 (NM_001256188:c.470G>A; p.Arg157His), along with a variant in the TERT promoter (C250T, NM_198253.2: c.-146G>A), were already present in primary O2005. Allele frequencies of the 11 variants were calculated to assess their potential as putative driver genes. A missense change in NDST4 (NM_022569:c.2392C>G; p.Leu798Val) on 4q exhibited an increasing allele frequency (~ 20%, primary O2005, 80%, recurrent O2010 and 100%, xenograft1), consistent with a selection event. Sequencing of NDST4 in a cohort of 15 oligodendrogliomas, however, revealed no additional cases with potential protein disrupting variants. Our analysis illuminated a tumor evolutionary series of events, which included 1p/19q codeletion, IDH1 R132H, and TERT C250T as early events, followed by loss of function of NDST4 and mutations in FUBP1 and CIC as late events.
Highlights
Few of the extensive number of mutations compiled for human tumors, since the advent of exome sequencing, have impacted our understanding of tumor biology like those in human diffuse low grade gliomas
One major difference was a gain of the chromosomal arm 4q in xenograft1, which could be the result of the outgrowth of a subclone that was either present but previously undetectable in recurrent O2010, or it represented the generation of a new clone altogether in the mouse
Exome sequencing coupled with array comparative genomic hybridization (CGH) performed on a rare oligodendroglioma xenograft revealed a highly stable genome relative to the recurrent human tumor from which it was derived
Summary
Few of the extensive number of mutations compiled for human tumors, since the advent of exome sequencing, have impacted our understanding of tumor biology like those in human diffuse low grade gliomas. These tumors represent a unique cancer subgroup largely because of a distinctive subset of variants, which includes isocitrate dehydrogenase 1/2 (IDH1/IDH2) [1,2,3]. These variants create a neomorphic enzyme that generates a metabolite, 2-hydroxyglutarate (2-HG), not normally detectable in the human brain [4]. There is a clear need to further delineate the significance of these mutations with regard to the biology of tumors in general and in the clinic
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