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The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection.

ABSTRACT: Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors and their matched recurrent counterparts. Molecular profiling of tumors was performed using multiplexed targeted deep sequencing of 409 well characterized cancer-associated genes, achieving a mean read depth of 1272 x. Three levels of evidence suggested an evolutionary pattern consistent with a response to therapy-mediated selection pressures exists in treated patients: 1) variant burden was reduced in recurrent tumors, 2) neutral evolutionary dynamics apparent in untreated tumors shifted toward a non-neutral mode of evolution in treated patients at recurrence, and 3) the recurrent tumor of one patient displayed an increased mutation rate attributable to a temozolomide-associated hypermutator phenotype. Our observations suggest that current treatment modalities are likely to fail in achieving long term remission with the majority of relapse samples containing distinct mutations when compared to primary diagnostic samples.

SUBMITTER: Muscat AM

PROVIDER: S-EPMC5814263 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection.

Muscat Andrea M AM Wong Nicholas C NC Drummond Katharine J KJ Algar Elizabeth M EM Khasraw Mustafa M Verhaak Roel R Field Kathryn K Rosenthal Mark A MA Ashley David M DM

Oncotarget 20171215 8

Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alteration ...[more]

PMID: 29487696

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Project description:Makorin ring finger proteins (MKRNs) are part the of ubiquitin-proteasome system; a complex system important for cell functions. Ubiquitin fate through proteolytic, non-proteolytic pathways varies, depending on covalent linkage between ubiquitin and protein substrates. Makorin ring finger protein 3 is an integral part of covalent linkage of ubiquitin to protein substrates. Similar to others imprinted genes, MKRN3 also evolve under positive selection; however, which codons are specifically selected in MKRN3 during evolution are needed to be explored. Different maximum-likelihood (ML) codon-based methodologies were used to ascertain positive selection signatures in 22 mammalian sequences of MKRN3 to probe an individual codon for positive selection signatures. By applying the HyPhy software package implemented in the Data Monkey Web Server and CODEML implemented in PAML, evolutionary analysis based on two Ml frameworks were conducted. The analysis was executed by comparing M1a against M2a, M7 against M8, and PAML models and 2∆Lnl (LRT) was resulted by likelihood logs. M1a contributed ω1 (dN/dS) with LRT value (∆Lnl) 12.01, and positive selection was found in M2a with ω3 = 2.23603. To further improve selection test, M8 was compared to M7 with 2∆Lnl (LRT) 30.17, and M8 showed positive selection with ω = 1.55759. The data were fit to M8 than M7, which suggests that M8 was the most significant model of selection. M8 was judged encouraging for this analysis and used to establish a positive selection of MKRN3 proteins. We found Gly312 as a positively selected amino acid in a zinc finger motif/Really Interesting New Gene (RING) finger motif; the former ones' region is involved in RNA binding and the later ones in ubiquitin ligase activity of the protein, vital for protein function. Selection analyses of MKRNs might advance the developments in unique approaches that could lead to genetic progress over the selection of superior individuals with the breeding values higher for certain traits as ancestries to get the next generation.

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The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection.

Publications

The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection.

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