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  • 1
    Online Resource
    Online Resource
    PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation
    Springer Science and Business Media LLC ; 2022
    In:  Nature Communications Vol. 13, No. 1 ( 2022-02-01)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-02-01)
    Abstract: The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-022-28198-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    BIOL-04. INTEGRATED COPY-NUMBER AND CANCER DEPENDENCY ANALYSIS REVEALS ALTERED SPLICEOSOME STOICHIOMETRY AS A NOVEL VULNERABILITY IN GENOMICALLY DISRUPTED CANCERS
    Oxford University Press (OUP) ; 2017
    In:  Neuro-Oncology Vol. 19, No. suppl_4 ( 2017-06), p. iv4-iv4
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 19, No. suppl_4 ( 2017-06), p. iv4-iv4
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/nox083.012
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 2094060-9
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  • 3
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    CovidCounties is an interactive real time tracker of the COVID19 pandemic at the level of US counties
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Data Vol. 7, No. 1 ( 2020-11-16)
    Details
    In: Scientific Data, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2020-11-16)
    Abstract: Management of the COVID-19 pandemic has proven to be a significant challenge to policy makers. This is in large part due to uneven reporting and the absence of open-access visualization tools to present local trends and infer healthcare needs. Here we report the development of CovidCounties.org, an interactive web application that depicts daily disease trends at the level of US counties using time series plots and maps. This application is accompanied by a manually curated dataset that catalogs all major public policy actions made at the state-level, as well as technical validation of the primary data. Finally, the underlying code for the site is also provided as open source, enabling others to validate and learn from this work.
    Type of Medium: Online Resource
    ISSN: 2052-4463
    URL: Article
    DOI: 10.1038/s41597-020-00731-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2775191-0
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  • 4
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    HGG-60. Structural variants shape driver combinations and outcomes in pediatric high-grade glioma
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i75-i76
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i75-i76
    Abstract: Pediatric high-grade gliomas (pHGGs), encompassing hemispheric and diffuse midline gliomas (DMGs), remain a devastating disease. The last decade has revealed oncogenic drivers including single nucleotide variants (SNVs) in histones. However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored due to limitations in early SV analysis approaches. Using SV algorithms, we recently created, we analyzed SVs in whole-genome sequences of 179 pHGGs including a novel cohort of treatment naïve samples–the largest WGS cohort assembled in adult or pediatric glioma. The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases, including a novel SV amplifying a MYC enhancer in the lncRNA CCDC26 in 12% of DMGs and revealing a more central role for MYC in these cancers than previously known. Applying de novo SV signature discovery, we identified five signatures including three (SVsig1-3) involving primarily simple SVs, and two (SVsig4-5) involving complex, clustered SVs. These SV signatures associated with genetic variants that differed from what was observed for SV signatures in other cancers, suggesting different links to underlying biology. Tumors with simple SV signatures were TP53 wild-type but were enriched with alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A, and RB1 early in tumor evolution, and with extrachromosomal amplicons that likely occurred later. All pHGGs exhibited at least one simple SV signature but complex SV signatures were primarily restricted to subsets of H3.3K27M DMGs and hemispheric pHGGs. Importantly, DMGs with the complex SV signatures SVsig4-5 were associated with shorter overall survival independent of histone type and TP53 status. These data inform the role and impact of SVs in gliomagenesis and mechanisms that shape them.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.275
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 5
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    Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of clinical data
    Springer Science and Business Media LLC ; 2023
    In:  npj Precision Oncology Vol. 7, No. 1 ( 2023-03-23)
    Details
    In: npj Precision Oncology, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2023-03-23)
    Abstract: The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is a rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of the electronic medical record and national payer data and found that FLC incidence is likely five to eight times higher than previous estimates. By employing unsupervised learning on clinical laboratory data from patients with hyperammonemia, we find that FLC-associated hyperammonemia mirrors metabolic dysregulation in urea cycle disorders. Our findings demonstrate that advanced computational analysis of rich clinical datasets can provide key clinical and biochemical insights into rare cancers.
    Type of Medium: Online Resource
    ISSN: 2397-768X
    URL: Article
    DOI: 10.1038/s41698-023-00371-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 6
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    Computational extraction and analysis of de-identified medical records to characterize hyperammonemia in patients with fibrolamellar carcinoma (FLC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e16169-e16169
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e16169-e16169
    Abstract: e16169 Background: Rare cancers including FLC make up 25% of adult tumors, but are difficult to study due to low incidence and incomplete case identification. FLC occurs in adolescents and young adults without liver dysfunction. Hyperammonemia has been frequently reported in FLC patients, but is poorly understood. Methods: Data from three clinical trials allowed us to establish the incidence of hyperammonemia (serum ammonia value 〉 75 µmol/L) in FLC. In these studies, FLC patients received everolimus, estrogen deprivation therapy (EDT) with leuprolide + letrozole or everolimus + EDT (Oncologist. 2020 25(11):925-e1603), ENMD-2076 (Oncologist. 2020 25(12):e1837-e1845), or neratinib (J Clin Oncol 39, 2021 (suppl 3; abstr 310); ammonia was tested prospectively in the latter two studies. To assess impacts of cancer therapy or liver dysfunction, we studied hyperammonemia in FLC and non-FLC patients at UCSF in parallel. Using Natural Language Processing (NLP) of pathology reports and oncology notes from 〉 2300 liver cancer patients from the last 12 years of UCSF records, we identified a cohort of patients with FLC, contrasting their laboratory data to all UCSF patients with ammonia testing for the last 10 years. We used leiden clustering and umap dimensionality reduction to contrast FLC and other patients to assess the clinical context of hyperammonemia. Results: Data from the 3 trials showed hyperammonemia in 10 of 32 (31.3%) FLC patients during study participation, independent of the therapy received. These patients exhibited hyperammonemia with varying levels, and at different points in their treatment. NLP identified 37 patients with FLC ( 〈 0.1% of liver cancer patients), with 33% showing hyperammonemia. Across all UCSF patients, we found 24,000 independent visits where ammonia was tested, with 〉 2400 demonstrating hyperammonemia. Using leidan clustering on all encounters with ammonia 〉 75 µmol/L, we found distinct subsets of hyperammonemia corresponding to known metabolic and physiologic processes (e.g., fulminant liver failure, tumor lysis syndrome, etc). FLC patients clustered separately from hepatocellular carcinoma patients with hyperammonemic encephalopathy due to cirrhosis. Conclusions: NLP of large EMRs is a valuable tool to study FLC, a rare cancer. Herein, we have defined hyperammonemia as a frequent event in FLC, not directly linked to hepatic dysfunction or individual therapies. Further investigation may determine whether hyperammonemia is related to FLC tumor biology.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.e16169
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 7
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    AN UNUSUAL CASE OF INNUMERABLE LUNG NODULES
    Elsevier BV ; 2019
    In:  Chest Vol. 156, No. 4 ( 2019-10), p. A703-
    Details
    In: Chest, Elsevier BV, Vol. 156, No. 4 ( 2019-10), p. A703-
    Type of Medium: Online Resource
    ISSN: 0012-3692
    URL: Article
    DOI: 10.1016/j.chest.2019.08.680
    RVK:
    XA 36340
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2007244-2
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  • 8
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    Abstract LB-227: Truncal activating MAPK and PI3K pathway alterations and exceptional response to dual pathway inhibition in anaplastic thyroid cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-227-LB-227
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-227-LB-227
    Abstract: Background: Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors, with a uniformly fatal prognosis. No effective systemic therapies exist. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR or combined RAF/MEK inhibition, but experienced a dramatic response when both drug regimens were combined. Methods and Results: Nine biopsies of the tumor were obtained between diagnosis and autopsy. Multi-region whole-exome sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways respectively. We performed the largest meta-analysis of ATC to date and found a 7.4% co-occurrence of MAPK and PI3K pathway alterations in ATC. We analyzed 5,255 cancer exomes in the Cancer Genome Atlas (TCGA) to determine whether similar cancer genomes occurred outside of anaplastic thyroid carcinoma. We identified 11 tumors with BRAF V600E and non-silent PIK3CA mutations. These results indicate that this genotype occurs in other cancers and may predict response to combined therapy. Conclusions and future directions: We have identified a patient with ATC who had a dramatic response to combined inhibition of the MAPK and PI3K pathways, whereas neither MAPK inhibition nor PI3K inhibition alone was sufficient to produce tumor regression. These observations suggest that MAPK and PI3K/MTOR pathway blockade represents an effective dual therapy aimed at the founding oncogenic lesions in a subset of ATC. Citation Format: William J. Gibson, Daniel T. Ruan, Vera A. Paulson, Justine A. Barletta, Glenn J. Hanna, Stefan Kraft, Antonio Calles, Matthew Nehs, Francis Moore, Amaro Taylor-Weiner, Jeremiah Wala, Travis Zack, Thomas Lee, Fiona Fennessy, Erik Alexander, Tom Thomas, Pasi Jäne, Levi Garraway, Scott Carter, Rameen Beroukhim, Jochen Lorch, Eliezer Van Allen. Truncal activating MAPK and PI3K pathway alterations and exceptional response to dual pathway inhibition in anaplastic thyroid cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-227.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-LB-227
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Topic modeling on clinical social work notes for exploring social determinants of health factors
    Oxford University Press (OUP) ; 2024
    In:  JAMIA Open Vol. 7, No. 1 ( 2024-01-04)
    Details
    In: JAMIA Open, Oxford University Press (OUP), Vol. 7, No. 1 ( 2024-01-04)
    Abstract: Existing research on social determinants of health (SDoH) predominantly focuses on physician notes and structured data within electronic medical records. This study posits that social work notes are an untapped, potentially rich source for SDoH information. We hypothesize that clinical notes recorded by social workers, whose role is to ameliorate social and economic factors, might provide a complementary information source of data on SDoH compared to physician notes, which primarily concentrate on medical diagnoses and treatments. We aimed to use word frequency analysis and topic modeling to identify prevalent terms and robust topics of discussion within a large cohort of social work notes including both outpatient and in-patient consultations. Materials and methods We retrieved a diverse, deidentified corpus of 0.95 million clinical social work notes from 181 644 patients at the University of California, San Francisco. We conducted word frequency analysis related to ICD-10 chapters to identify prevalent terms within the notes. We then applied Latent Dirichlet Allocation (LDA) topic modeling analysis to characterize this corpus and identify potential topics of discussion, which was further stratified by note types and disease groups. Results Word frequency analysis primarily identified medical-related terms associated with specific ICD10 chapters, though it also detected some subtle SDoH terms. In contrast, the LDA topic modeling analysis extracted 11 topics explicitly related to social determinants of health risk factors, such as financial status, abuse history, social support, risk of death, and mental health. The topic modeling approach effectively demonstrated variations between different types of social work notes and across patients with different types of diseases or conditions. Discussion Our findings highlight LDA topic modeling’s effectiveness in extracting SDoH-related themes and capturing variations in social work notes, demonstrating its potential for informing targeted interventions for at-risk populations. Conclusion Social work notes offer a wealth of unique and valuable information on an individual’s SDoH. These notes present consistent and meaningful topics of discussion that can be effectively analyzed and utilized to improve patient care and inform targeted interventions for at-risk populations.
    Type of Medium: Online Resource
    ISSN: 2574-2531
    URL: Article
    DOI: 10.1093/jamiaopen/ooad112
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
    detail.hit.zdb_id: 2940623-7
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  • 10
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    HGG-41. STRUCTURAL VARIANT DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii351-iii351
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii351-iii351
    Abstract: Driver single nucleotide variants (SNV) and somatic copy number aberrations (SCNA) of pediatric high-grade glioma (pHGGs), including Diffuse Midline Gliomas (DMGs) are characterized. However, structural variants (SVs) in pHGGs and the mechanisms through which they contribute to glioma formation have not been systematically analyzed genome-wide. METHODS Using SvABA for SVs as well as the latest pipelines for SCNAs and SNVs we analyzed whole-genome sequencing from 174 patients. This includes 60 previously unpublished samples, 43 of which are DMGs. Signature analysis allowed us to define pHGG groups with shared SV characteristics. Significantly recurring SV breakpoints and juxtapositions were identified with algorithms we recently developed and the findings were correlated with RNAseq and H3K27ac ChIPseq. RESULTS The SV characteristics in pHGG showed three groups defined by either complex, intermediate or simple signature activities. These associated with distinct combinations of known driver oncogenes. Our statistical analysis revealed recurring SVs in the topologically associating domains of MYCN, MYC, EGFR, PDGFRA & MET. These correlated with increased mRNA expression and amplification of H3K27ac peaks. Complex recurring amplifications showed characteristics of extrachromosomal amplicons and were enriched in coding SVs splitting protein regulatory from effector domains. Integrative analysis of all SCNAs, SNVs & SVs revealed patterns of characteristic combinations between potential drivers and signatures. This included two distinct groups of H3K27M DMGs with either complex or simple signatures and different combinations of associated variants. CONCLUSION Recurrent SVs associate with signatures shaped by an underlying process, which can lead to distinct mechanisms to activate the same oncogene.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.322
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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