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  • Oxford University Press (OUP)  (86)
  • 1
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    HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i43-i44
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i43-i44
    Abstract: PDGFRA is commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a fatal disease with no current options for cure. We performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grade glioma cases which revealed PDGFRA genomic alterations in ~15% of patients. H3K27M DMGs had significantly higher PDGFRA expression compared to H3 wild-type tumors regardless of genomic alteration. Tumors with PDGFRA gene amplification demonstrated significantly elevated PDGFRA expression in both H3K27M DMGs and H3 wild-type pHGGs relative to tumors with wild-type or point mutated PDGFRA. We tested a range of PDGFRA inhibitors against a panel of patient derived pediatric H3K27M DMG, pHGG, and adult HGG. Amongst the inhibitors tested, avapritinib, a potent small molecule inhibitor with relatively selective activity against both wild-type and mutant PDGFRA showed potent toxicity against a wide array of pediatric and adult cell lines. This molecule also demonstrated supra-micromolar blood brain barrier penetration in pre-clinical in vivo models, and demonstrated significant decrease in tumor growth and improved survival in orthotopic mouse xenograft models. Finally, building on this preclinical activity, we report the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib usage showed no significant acute toxicities within this patient cohort. Most importantly, our preliminary data reveal radiographic response evaluated by RAPNO criteria in 50% of patients, a striking outcome rarely seen in this patient population. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced promising clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in pediatric high grade glioma.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.168
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2094060-9
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  • 2
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    VariantBam: filtering and profiling of next-generational sequencing data using region-specific rules
    Oxford University Press (OUP) ; 2016
    In:  Bioinformatics Vol. 32, No. 13 ( 2016-07-01), p. 2029-2031
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 32, No. 13 ( 2016-07-01), p. 2029-2031
    Abstract: We developed VariantBam, a C ++ read filtering and profiling tool for use with BAM, CRAM and SAM sequencing files. VariantBam provides a flexible framework for extracting sequencing reads or read-pairs that satisfy combinations of rules, defined by any number of genomic intervals or variant sites. We have implemented filters based on alignment data, sequence motifs, regional coverage and base quality. For example, VariantBam achieved a median size reduction ratio of 3.1:1 when applied to 10 lung cancer whole genome BAMs by removing large tags and selecting for only high-quality variant-supporting reads and reads matching a large dictionary of sequence motifs. Thus VariantBam enables efficient storage of sequencing data while preserving the most relevant information for downstream analysis. Availability and implementation: VariantBam and full documentation are available at github.com/jwalabroad/VariantBam. Contact:  rameen@broadinstitute.org Supplementary information:  Supplementary data are available at Bioinformatics online.
    Type of Medium: Online Resource
    ISSN: 1367-4811 , 1367-4803
    URL: Article
    DOI: 10.1093/bioinformatics/btw111
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 1468345-3
    SSG: 12
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  • 3
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    Tangent normalization for somatic copy-number inference in cancer genome analysis
    Oxford University Press (OUP) ; 2022
    In:  Bioinformatics Vol. 38, No. 20 ( 2022-10-14), p. 4677-4686
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 38, No. 20 ( 2022-10-14), p. 4677-4686
    Abstract: Somatic copy-number alterations (SCNAs) play an important role in cancer development. Systematic noise in sequencing and array data present a significant challenge to the inference of SCNAs for cancer genome analyses. As part of The Cancer Genome Atlas, the Broad Institute Genome Characterization Center developed the Tangent normalization method to generate copy-number profiles using data from single-nucleotide polymorphism (SNP) arrays and whole-exome sequencing (WES) technologies for over 10 000 pairs of tumors and matched normal samples. Here, we describe the Tangent method, which uses a unique linear combination of normal samples as a reference for each tumor sample, to subtract systematic errors that vary across samples. We also describe a modification of Tangent, called Pseudo-Tangent, which enables denoising through comparisons between tumor profiles when few normal samples are available. Results Tangent normalization substantially increases signal-to-noise ratios (SNRs) compared to conventional normalization methods in both SNP array and WES analyses. Tangent and Pseudo-Tangent normalizations improve the SNR by reducing noise with minimal effect on signal and exceed the contribution of other steps in the analysis such as choice of segmentation algorithm. Tangent and Pseudo-Tangent are broadly applicable and enable more accurate inference of SCNAs from DNA sequencing and array data. Availability and implementation Tangent is available at https://github.com/broadinstitute/tangent and as a Docker image (https://hub.docker.com/r/broadinstitute/tangent). Tangent is also the normalization method for the copy-number pipeline in Genome Analysis Toolkit 4 (GATK4). Supplementary information Supplementary data are available at Bioinformatics online.
    Type of Medium: Online Resource
    ISSN: 1367-4803 , 1367-4811
    URL: Article
    DOI: 10.1093/bioinformatics/btac586
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1468345-3
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  • 4
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    DIPG-53. CHARACTERIZING THE ROLE OF PPM1D MUTATIONS IN THE PATHOGENESIS OF DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGS)
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii297-iii297
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii297-iii297
    Abstract: We have previously found that up to 15% of all DIPGs harbor mutations in PPM1D, resulting in the expression of an activated and truncated PPM1D (PPM1Dtr). Here we evaluate the mechanisms through which PPM1Dtr enhances glioma formation and identify its associated therapeutic vulnerabilities. METHODS We have developed multiple in vitro and in vivo models of PPM1D-mutant DIPGs and applied quantitative proteomic and functional genomic approaches to identify pathways altered by PPM1Dtr and associated dependencies. RESULTS PPM1D mutations are clonal events that are anti-correlated to TP53 mutations. We find ectopic expression of PPM1Dtr to be sufficient to enhance glioma formation and to be necessary in PPM1D-mutant DIPG cells. In addition, endogenous truncation of PPM1D is sufficient to enhance glioma formation in the presence of mutant H3F3A and PDGFRA. PPM1Dtr overexpression attenuates g-H2AX formation and suppresses apoptosis and cell-cycle arrest in response to radiation treatment. Deep scale phosphoproteomics analyses reveal DNA-damage and cell cycle pathways to be most significantly associated with PPM1Dtr. Furthermore, preliminary analysis of genome-wide loss-of-function CRISPR/Cas9 screens in isogenic GFP and PPM1Dtr overexpressing mouse neural stem cells reveal differential dependency on DNA-damage response genes in the PPM1Dtr overexpressing cells. Consistent with PPM1D’s role in stabilizing MDM2, PPM1D-mutant DIPG models are sensitive to a panel of MDM2 inhibitors (Nutlin-3a, RG7388, and AMG232). CONCLUSION Our study shows that PPM1Dtr is both an oncogene and a dependency in PPM1D- mutant DIPG, and there are novel therapeutic vulnerabilities associated with PPM1D that may be exploited.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.098
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 5
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    EPCO-21. CORE REGULATORY CIRCUIT TRANSCRIPTION FACTORS DRIVE EXPRESSION FROM HIGH LEVEL AMPLICONS IN PEDIATRIC HIGH-GRADE GLIOMAS
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi6-vi6
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi6-vi6
    Abstract: Pediatric High-Grade Gliomas (pHGGs) show recurrent high-level amplifications around the oncogenes MET, MYCN and EGFR. However what drives expression of the oncogenes from these amplicons remains unclear. We aim to discover enhancers on these amplicons that are responsible for oncogene expressions and the core regulatory transcription factors (TFs) they bind. METHOD Using RNA-seq from 12 pHGG cell lines, we identified groups of high and low-expressing pHGG lines for MET, MYCN and EGFR. We then compared the H3K27Ac ChIP-seq between the two groups using diffbind. This allowed us to identify statistically significant peaks that are differentially activated in the oncogene-high v.s. oncogene-low expressing groups. Additionally, we overlapped the positions of these candidate oncogene enhancers with the regions that are recurrently incorporated into high-level amplicons based on published whole genome sequencing data. Using a previously defined set of core regulatory TFs we determined which TF binds the amplified oncogene enhancers and could be driving oncogenic expressions of MET, MYCN and EGFR in pHGGs. RESULTS We identify 3 cell lines for both the high- and low-expressing groups for each oncogene. Cell lines with high expression of the oncogene showed distinct enhancers with significant enrichment in H3K27Ac compared to the cell lines with low expression for each oncogene. Of all enhancers with enrichment high oncogene expression groups those with binding sites for known pHGG core regulatory circuit TF were preferentially incorporated into the high-level amplicons of the oncogene. We also identified core TFs that bind enhancers for MYCN, EGFR and MET as well as core TFs that are unique to a single oncogene. CONCLUSION We identified candidate core transcription factor that drives expression of multiple oncogenes in pHGG. These could serve as a potential novel therapeutic target for pHGGs with addiction to MYCN or RTK signaling.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.020
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 6
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    BIOM-47. PREDICTORS OF SEIZURE AT ONSET USING A FUNCTIONAL VARIANT ANALYSIS OF TARGETED NEXT GENERATION SEQUENCING IN GBM
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii15-vii15
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii15-vii15
    Abstract: Adverse events (AE) including seizures cause significant morbidity in patients with GBM. We propose a novel method for assessing genomic predictors of AEs using results from a clinical targeted sequencing platform with variant function analysis. METHODS We identified 1,011 consecutive adult patients with newly diagnosed, histologically confirmed IDH-wildtype GBM with targeted exome NGS (Oncopanel) at Dana-Farber Cancer Institute from 2013-2019. Seizure at presentation was retrospectively identified as an AE. Biologic function (high loss, low loss, neutral, low gain and high gain) was assigned to variants using a three-tiered approach leveraging a genetic variant database (OncoKB), followed by analysis using protein prediction tools (Sift, Polyphen2 and Provean). Univariate logistic regression was performed for each relevant altered gene against the outcome of interest with false-discovery rate correction. Genes associated with seizure at presentation were included iteratively in a multivariate logistic model including other predictors of the outcome. RESULTS Our analysis included 470 GBM patients with 107 genes and 12 whole chromosome or arm level candidate variants covered by all versions of Oncopanel and with & gt;10% alteration. Seizure at presentation occurred in 143/463 patients (31%) and was associated with EGFR amplification (high gain) (OR: 2.76, 95% CI: 1.4-5.3, p = 0.04). In a multivariate analysis (including age, sex, and preoperative tumor volume), EGFR amplification remained statistically significant (OR: 1.5, 95% CI: 1.0-2.2, p = 0.03). CONCLUSION Genomic biomarkers based on functional variant analysis of a routine clinical panel may predict adverse events in GBM. Seizure at presentation was independently associated with EGFR amplification. Our ongoing analysis will look at predictors of myelosuppression, thromboembolism, pseudoprogression and early progression using a similar approach. Identifying molecular risk factors could improve the management of patients through supportive care and consideration of prophylactic therapies.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.057
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    PATH-15. THE PROGNOSTIC IMPLICATION OF MGMT PROMOTER METHYLATION IN IDH-MUTANT GLIOMAS
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii153-vii153
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii153-vii153
    Abstract: MGMT promoter methylation in IDH-mutant gliomas was associated with improved survival in a recent study (PMID 35386566) but did not account for the updated WHO classification of CNS tumors. We evaluated the prognostic value of MGMT methylation in IDH-mutant gliomas incorporating the 2021 WHO classification. METHODS We retrospectively identified 431 patients with IDH-mutant gliomas treated at a single institution from 2010-2020. Kaplan-Meier method was used to estimate OS and PFS rates. Log-Rank test was used to evaluate differences between groups. RESULTS Median age was 36.2 years. MGMT promoter was methylated in 49.6%, unmethylated in 17.2%, partially methylated in 6.7%, and untested in 26.5%. Histological diagnosis was consistent with astrocytoma in 45.7%, oligodendroglioma in 33.9%, glioblastoma in 16.4%, and oligoastrocytoma in 4%. After accounting for 1p/19q and CDKN2A statuses, 190 patients had an integrated diagnosis of astrocytoma, grade 2 or 3; 94 had astrocytoma, grade 4; and 147 had oligodendroglioma, grade 2 or 3. There were 101 death events. Median OS was 33.36 years and median PFS was 5.67 years in MGMT methylated gliomas, compared to median OS of 12.54 years (p=0.0064) and median PFS of 3.91 years (p=0.0034) in unmethylated tumors. Upon univariate subgroup analysis, MGMT methylation was associated with significantly longer OS in histological astrocytomas, grade 2 or 4. However, when stratifying patients according to 2021 WHO classification of CNS tumors, there was no significant difference in OS between MGMT methylated and unmethylated astrocytomas or oligodendrogliomas, irrespective of WHO grade. CONCLUSION MGMT promoter methylation was associated with prolonged OS in histological astrocytomas, IDH-mutant. However, MGMT status did not impact survival after incorporating 2021 WHO classification of CNS tumors, suggesting that 1p/19q co-deletion and CDKN2A homozygous deletion are stronger prognostic factors in our cohort. The number of survival events was limited; larger datasets are required for more definitive conclusions.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.588
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 8
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    EXTH-95. UNCOVERING THERAPEUTIC VULNERABILITIES IN MISMATCH REPAIR-DEFICIENT GLIOMAS
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii231-vii232
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii231-vii232
    Abstract: Approximately 25% of recurrent gliomas exhibit hypermutation, which is most often acquired in chemotherapy sensitive gliomas post-treatment with standard of care alkylating agent temozolomide, Intriguingly, nearly all of these recurrent hypermutant tumors harbor deficiencies in mismatch repair (MMR) genes. Unlike other MMR-deficient cancers, hypermutant gliomas do not exhibit detectable microsatellite instability (MSI) at the population level, and do not share similar dependencies. Thus, strategies to therapeutically target MMR-deficient and hypermutant gliomas are urgently needed, and likely to impact many patients. To evaluate vulnerabilities associated with MMR-deficient gliomas, we have generated isogenic MMR-deficient models by systematic ablation of core MMR genes MSH2, MSH6, MLH1, and PMS2, in multiple patient-derived glioma cell lines using a robust all-in-one CRISPR-Cas9 system. We characterized these isogenic MMR-deficient glioma lines in comparison to respective MMR-proficient control line by performing differential gene expression analysis and subsequent gene set enrichment analyses. Our analyses reveal in an unbiased fashion an enrichment of several hallmark gene sets including cell cycle control and DNA repair in the MMR-deficient cell lines. We performed a CRISPR-Cas9 knockout screen in these MMR deficient and hypermutant models and identified candidate genes involved in DNA repair, cell cycle, RNA metabolism and other pathways as preferential dependencies in the MMR-deficient glioma cells. We also screened multiple MMR-deficient isogenic models against the high-throughput drug repurposing (REPO) chemical library and our preliminary results reveal a number of compounds from a variety of drug classes that selectively kill the MMR-deficient glioma cells, indicating that the loss of MMR confers differential dependencies to these small molecule inhibitors. The candidate drugs and genes identified from these high-throughput assays are currently being subjected to further validation, and they possibly will help us identify novel therapeutic strategies or improve existing therapeutic strategies to target recurrent MMR-deficient gliomas.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.893
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 9
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    LG-02MYB-QKI REARRANGEMENTS IN ANGIOCENTRIC GLIOMA DRIVE TUMORIGENICITY THROUGH A TRIPARTITE MECHANISM
    Oxford University Press (OUP) ; 2016
    In:  Neuro-Oncology Vol. 18, No. suppl 3 ( 2016-06), p. iii78.2-iii78
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 18, No. suppl 3 ( 2016-06), p. iii78.2-iii78
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/now075.02
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
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  • 10
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    Leveraging molecular datasets for biomarker-based clinical trial design in glioblastoma
    Oxford University Press (OUP) ; 2017
    In:  Neuro-Oncology Vol. 19, No. 7 ( 2017-07), p. 908-917
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 19, No. 7 ( 2017-07), p. 908-917
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/now312
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
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