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Publications
Publications (78)
Background
Cancer immunotherapies including immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapy have shown variable response rates in paediatric patients highlighting the need to establish robust biomarkers for patient selection. While the tumour microenvironment in adults has been widely studied to delineate determinant...
Pediatric central nervous system cancers are the leading disease-related cause of death in children and there is urgent need for curative therapeutic strategies for these tumors. To address the urgency, Children’s Brain Tumor Network (CBTN) has advanced an open science model to accelerate the research discovery for pediatric brain tumors. In first...
Pediatric brain tumor preclinical development has suffered from the lack of robust in vitro and in vivo models that span the large number of brain tumor histologies. Opportunities for precision medicine approaches for solid and brain tumors are expanding, including immunotherapies, so it is essential to maximize access to preclinical models for stu...
The genetic contribution of rare pathogenic germline variation in cancer patients without a family history remains unclear. We sought to characterize the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in pediatric brain tumor patients. Paired tumor and normal whole genome or ex...
Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor b...
Introduction: Immunotherapeutic strategies have produced remarkable results in some malignancies. However, optimal cell surface targets in many childhood cancers remain elusive and tools for novel target discovery are limited. We developed a proteogenomic approach to identify high confidence cell surface proteins for immunotherapy development and a...
Brain tumors are the leading cause of disease-related death in children and young adults ages 0-19 in largely populated countries such as the United States. In one year alone, 4,000 children and young adults will be diagnosed with a brain or central nervous system tumor in the United States. Brain tumors are complex and difficult to treat in growin...
The Gabriella Miller Kids First Pediatric Research Program (Kids First) has enabled genomic and transcriptomic characterization across a multitude of pediatric diseases at an unprecedented scale. This includes both pediatric cancer cohorts and structure birth defect cohorts, as co-occurrences of these suggest a shared context of developmental biolo...
Pediatric central nervous system (CNS) cancers are the leading disease-related cause of death in children and there is urgent need for curative therapeutic strategies for these tumors. To address the urgency, Children’s Brain Tumor Network (CBTN) has advanced an open science model to accelerate the research discovery for pediatric brain tumors. In...
Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-inst...
Patients with non-small cell lung cancer (NSCLC) who have distant metastases have a poor prognosis. To determine which genomic factors of the primary tumor are associated with metastasis, we analyzed data from 759 patients originally diagnosed with stage I–III NSCLC as part of the AACR Project GENIE Biopharma Collaborative consortium. We found that...
Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-inst...
To inform immunotherapy approaches in children, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve pediatric nervous system tumours (pedNST) spanning 12 cancer types from three public data sets. Within pedNST, we uncovered four broad immune clusters: Pediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (4...
The Gabriella Miller Kids First Pediatric Research Program (Kids First) aims at facilitating researchers to uncover new insights into the biology of childhood cancer (CC) and structural birth defects (SBD), including the discovery of shared genetic pathways between these disorders. Kids First has two initiatives, which are whole genome sequencing (...
INTRODUCTION: Recent clinical trials of immune checkpoint inhibitors indicated 5-11% response rate in pediatric patients depending on cancer type and expression of target proteins. Currently, a systematic analysis characterizing the immune microenvironment of childhood tumors is lacking. The main objective of this study is to uncover the features o...
The Gabriella Miller Kids First Pediatric Research Program (Kids First) aims at facilitating researchers to uncover new insights into the biology of childhood cancer (CC) and structural birth defects (SBD). Kids First has two initiatives, i) whole genome sequencing of biospecimens from families with CC/SBD, and ii) establishing Kids First Data Reso...
The growing number of next-generation sequencing (NGS) data presents a unique opportunity to study the combined impact of mitochondrial and nuclear-encoded genetic variation in complex disease. Mitochondrial DNA variants and in particular, heteroplasmic variants, are critical for determining human disease severity. While there are approaches for ob...
Germline variants are known to contribute to the pathogenesis of specific central nervous system (CNS) tumor subtypes; however, a large pan-pediatric brain and nervous system cancer germline susceptibility study has not been performed. To define the prevalence and spectrum of pathogenic variants in known cancer predisposition genes (CPGs; n=200), w...
There is a growing role for mutations affecting histone linker and histone core-encoding genes across several adult and pediatric cancers. However, the extent to which somatic histone mutations may bridge across different cancers as common tumorigenic events – particularly in the context of pediatric CNS tumors – remains unclear. To address this kn...
Pediatric brain tumors comprise a heterogeneous molecular and histological landscape that challenges most current precision-medicine approaches. While recent large-scale efforts to molecularly characterize distinct histological entities have dramatically advanced the field’s capacity to classify and further define molecular subtypes, developing the...
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive, childhood brainstem cancer with a median overall survival of 10 months post diagnosis. Remarkably, 80–90% of patients harbor recurring point mutation in histone H3, which induces a lysine for methionine substitution at amino acid 27 (H3K27M) in either H3.1 (HIST1H3B ~25%) or H3.3 (H3F3...
Background
Gene fusion events are significant sources of somatic variation across adult and pediatric cancers and are some of the most clinically-effective therapeutic targets, yet low consensus of RNA-Seq fusion prediction algorithms makes therapeutic prioritization difficult. In addition, events such as polymerase read-throughs, mis-mapping due t...
Fewer than 1% of children diagnosed with diffuse-midline glioma (DMG) survive for more than 5 years, because no effective therapies exist for these patients. Here, we sought to identify and characterize mechanisms of aberrant splicing (AS) in primary DMG tumors. We observed transcriptome-wide AS (9,805 differential splicing variations in 4,734 gene...
We performed a comprehensive proteogenomic analysis across seven childhood brain tumors for a deeper understanding of their functional biology. Whole genome sequencing, RNAseq, quantitative proteomic profiling and phosphoproteomics were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytoma (93),...
The Children’s Brain Tumor Network (formerly known as Children’s Brain Tumor Consortium- CBTTC) is a global organization pioneering a model of open-science medical research to improve treatment and discover cures. Started in 2011, our objective was to utilize a regulatory, agreement, and governance architecture to remove existing research barriers...
Since launching to the public in September 2018, the Gabriella Miller Kids First Data Resource Center (DRC) has made an increasing number of pediatric genomic studies available to the research community. Currently, 1.3 PBs of genomic and clinical data drawn from 12,000 participants are available across a variety of pediatric cancer and structural b...
We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16...
We performed a comprehensive proteogenomic analysis across seven major types of childhood brain tumors for a deeper understanding of their functional biology. Whole genome seq, RNAseq, quantitative proteomic and phosphoproteomic profiling were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytom...
Introduction: Immune checkpoint inhibition is a novel approach of restimulating immune cells to overcome immunosuppressive microenvironment in tumors and has shown significant clinical benefit in 20-40% of adult patients. Although this success in adult cancers has resulted in a plethora of immunogenomic efforts to delineate mechanisms of response,...
Background:
Pediatric high-grade gliomas (pHGGs) are incurable malignant brain cancers. Clear somatic genetic drivers are difficult to identify in the majority of cases. We hypothesized that this may be due to the existence of germline variants that influence tumor etiology and/or progression and are filtered out using traditional pipelines for so...
Background
Gene fusion events are a significant source of somatic variation across adult and pediatric cancers and have provided some of the most effective clinically relevant therapeutic targets, yet computational algorithms for fusion detection from RNA sequencing data show low overlap of predictions across methods. In addition, events such as po...
BACKGROUND
Pediatric high grade glioma (pHGG) remains a fatal disease. Access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first...
Childhood cancers and structural birth defects share a common context of altered developmental biology, but the potential role of shared, genetic alterations and/or pathways across pediatric cancers and birth defects is not well explored. It is increasingly critical that genomic data are paired with high-quality clinical data to drive translational...
The Pediatric Brain Tumor Atlas (PBTA) is a cloud-based, cross-platform, and data-rich collaborative effort to accelerate discoveries for therapeutic intervention in children diagnosed with brain tumors. Pediatric brain tumors are the leading cause of disease-related death in children and despite advances in therapy, morbidity and mortality rates r...
Gabriella Miller Kids First Pediatric Research Program (GMKF) is a nation-wide, multi-year initiative focused on the integration of large-scale clinically annotated genomic data for childhood cancers and structural birth defects supported by the NIH Common Fund. Awarded by GMKF, the Kids First Data Resource Center (DRC) is tasked to build infrastru...
Gabriella Miller Kids First Pediatric Research Program (GMKF) is a nation-wide, multi-year initiative focused on the integration of large-scale clinically annotated genomic data for childhood cancers and structural birth defects supported by the NIH Common Fund. Awarded by GMKF, the Kids First Data Resource Center (DRC) is tasked to build infrastru...
Introduction: Immune repertoire is a highly diverse pool of B and T cell receptors (B/TCR) that determine boundaries of immune surveillance. Pre-existing immune clones within Tumor MicroEnvironment (TME) suggest existence of a functional antigen presenting machinery and recognizing T cells, which fail to eliminate tumor, likely due to immunosuppres...
The Pediatric Brain Tumor Atlas (PBTA) is a cloud-based, cross-platform, and data-rich collaborative effort to accelerate discoveries for therapeutic intervention in children diagnosed with brain tumors. Pediatric brain tumors are the leading cause of disease-related death in children and despite advances in therapy, morbidity and mortality rates r...
Childhood cancers and structural birth defects share a common context of altered developmental biology, but the potential role of shared, genetic alterations and/or pathways across pediatric cancers and birth defects is not well explored. It is increasingly critical that genomic data are paired with high-quality clinical data to drive translational...
Background: Pediatric high grade glioma (pHGG) remains a fatal disease. Increased access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children's Brain Tumor Tissue Consortium (CBTTC) from...
Meningiomas are the most common primary brain tumor of adults. The majority are benign (WHO grade I), with a mostly indolent course; 20% of them (WHO grade II and III) are, however, considered aggressive and require a more complex management. WHO grade II and III tumors are heterogeneous and, in some cases, can develop from a prior lower grade meni...
PURPOSE: Pediatric high grade glioma (pHGG) remains a fatal disease. Increasing the number of patient derived tumor models and reagents will encourage research in pHGG and support the translation of basic science research discoveries. This work describes a recent multi-institution initiative to provide such a resource. METHODS: pHGG tumors with ass...
Childhood cancers and structural birth defects share a common context of altered developmental biology, but the potential role of shared, genetic alterations and/or pathways across pediatric cancers and birth defects is not well explored. It is increasingly critical that genomic data are paired with high-quality clinical data to drive translational...
OBJECTIVE: We evaluated the impact on overall survival at 12 months (OS12) of a personalized therapy plan based on tumor/germline whole exome (WES) and tumor RNA sequencing (RNAseq) of diffuse intrinsic pontine glioma (DIPG). METHODS: We enrolled newly diagnosed DIPG patients ≤ 25 years of age. Tumors were sequenced and drug selection was performed...
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is an infiltrative, inoperable midline tumor with devastating outcomes. We have recently completed a prospective clinical trial for children and young adults with newly diagnosed DIPG that included clinical whole exome sequencing (WES) and RNA sequencing (RNAseq) of tumors and development of a per...
RATIONALE: One of the major hurdles in developing effective treatment for children with DIPG includes the lack of extensive combinatorial studies targeting major driver oncogenic pathways. Combination of H3K27M and TP53 mutations are found in over 50% of DIPG tumors, however, there is a lack of effective combinatorial precision therapy. METHODS: Ti...
Genomic characterization has allowed for the differentiation of different tumor types based upon the abundance of gene transcripts. However, owing to the many layers of regulation between transcript and the post-translationally modified protein, the functional moiety of the cell, it has been challenging to extrapolate biology from these transcripti...
The Pediatric Brain Tumor Atlas (PBTA), created as a multi-center effort by the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) and supported by the Gabriella Miller Kids First Data Resource Center (DRC), has the initial goal of comprehensively characterizing over 1,600 clinically annotated pe...
Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones....
This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared with WES to...
The pediatric cancer genome is severely under-represented in genomic warehouses as existing data portals have primarily focused on adult malignancies. This is markedly more pronounced for pediatric brain tumor data as large-scale pediatric initiatives like TARGET do not capture these tumors. To address this unmet need, we have developed a new cance...
BACKGROUND
All cancers acquire a mechanism of telomere maintenance (TMM) for genomic stability and unlimited replicative potential. Some cancers, including a subset of pediatric brain tumors, use the TMM of alternative lengthening of telomeres (ALT). However, there are few cancer cell lines with ALT, representing a mixture of histotypes. We aim to...
Childhood cancers and structural birth share a common context of context in developmental biology that remains poorly defined. Indeed, epidemiologically, pediatric central nervous system tumors are some of the most frequently co-occurring cancers in children with birth defects. While researchers have been increasingly identifying the underlying bio...
Identifying selective immunotherapy targets for clinical development in pediatric brain tumors poses a number of challenges. Growing publicly available datasets complemented by large scale cohorts of RNA sequencing data derived from cross-disease cohorts in the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pacific Pediatric Neuro-Oncology Co...
Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradox...
Pediatric brain tumors are the leading cause of disease-related death in children. However, despite large scale data-driven efforts for pediatric cancers by the NIH (e.g. TARGET, Therapeutically Applicable Research To Generate Effective Treatments), public access to large-scale pediatric brain tumor genomic data remains limited. As a result, precis...
CAVATICA (cavatica.org) was developed to address the lack of open access large scale pediatric cancer genomic datasets for the research community. As the first of its kind pediatric genomic portal, CAVATICA empowers data upload, sharing, and creation of pipelines, data, algorithms, visualizations, and hypotheses. Building upon the need for pediatri...
Meningiomas are the most common adult primary tumors in the nervous system, accounting for more than 30% of all brain tumors. Meningiomas arise from arachnoid cells and while the majority is benign (WHO Grade I), about 20% (WHO Grades II and III) are considered aggressive. Grade II and III tumors are heterogeneous and present characteristics of agg...
Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studie...
INTRODUCTION: Activating BRAF-fusion mutations occur frequently in pediatric low-grade gliomas (PLGGs). We have previously shown targeting of KIAA1549-BRAF fusion by PLX4720, the research analog of vemurafenib, results in paradoxical activation of the mitogen activated protein kinase (MAPK) signal cascade. We hypothesized that BRAF-fusions could be...
RNA editing is a post-transcriptional event that recodes hereditary information. Here we describe a comprehensive profile of the RNA editome of a male Han Chinese individual based on analysis of ∼767 million sequencing reads from poly(A)(+), poly(A)(-) and small RNA samples. We developed a computational pipeline that carefully controls for false po...
