A5023009480- Cancer Genomics and Diagnostics
- Genetics, Bioinformatics, and Biomedical Research
- Bioinformatics and Genomic Networks
- Prostate Cancer Treatment and Research
- Genetic factors in colorectal cancer
- Cancer, Lipids, and Metabolism
- BRCA gene mutations in cancer
- Testicular diseases and treatments
- Single-cell and spatial transcriptomics
- Prostate Cancer Diagnosis and Treatment
- Lung Cancer Treatments and Mutations
- Computational Drug Discovery Methods
- Genomic variations and chromosomal abnormalities
- Chromatin Remodeling and Cancer
- Cancer Cells and Metastasis
- Evolution and Genetic Dynamics
- Cancer Immunotherapy and Biomarkers
- CRISPR and Genetic Engineering
- Neuroblastoma Research and Treatments
- Amphibian and Reptile Biology
- Epigenetics and DNA Methylation
- Sulfur Compounds in Biology
- Cutaneous Melanoma Detection and Management
- Radiopharmaceutical Chemistry and Applications
- Insect Resistance and Genetics
Harvard University
2017-2025
Dana-Farber Cancer Institute
2020-2025
Broad Institute
2020-2025
Dana-Farber Brigham Cancer Center
2020-2023
Brigham and Women's Hospital
2020-2023
Harvard University Press
2018
Abstract The determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge 1,2 . Recent advances interpretability machine learning models as applied to biomedical problems may enable discovery prediction genomics 3–5 Here we developed P-NET—a biologically informed deep model—to stratify patients with by treatment-resistance state evaluate drivers treatment resistance for therapeutic targeting through...
Abstract Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response immune checkpoint inhibitors 1 . Cellular programs driving in both cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma pervasively coexpressed multiple...
Abstract Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes a range human NECs show convergence to activation common epigenetic program. With particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), analyze cell lines, patient-derived xenograft (PDX) models samples existence two distinct NEPC...
Abstract Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). synthesis of GSH non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). imbalance implicated in many diseases, but requirement for adult tissues unclear. To interrogate this, we have developed a series vivo models induce Gclc deletion animals. We find that essential lipid abundance vivo. levels are highest liver tissue, which also hub production. While loss does...
Abstract Motivation Large-scale sequencing studies have created a need to succinctly visualize genomic characteristics of patient cohorts linked widely variable phenotypic information. This is often done by visualizing the co-occurrence variants with comutation plots. Current tools lack ability create highly customizable and publication quality plots from arbitrary user data. Results We developed CoMut, stand-alone, object-oriented Python package that creates input data, including...
High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants these outcomes are largely unknown. Here, we perform whole-exome transcriptome sequencing on pre-treatment multi-regional tumor...
Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial using genome sequencing 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered sex-biased association between very large (>1 megabase) chromosomal abnormalities increased in male children. The overall impact SVs was greatest neuroblastoma, where uncovered burdens ultrarare...
With the growth of clinical cancer single-cell RNA sequencing studies, robust differential expression methods for case/control analyses (e.g., treatment responders vs. non-responders) using gene signatures are pivotal to nominate hypotheses further investigation. However, many commonly used produce a large number false positives, do not adequately represent patient-specific hierarchical structure data, or account sample-driven confounders. Here, we present nonparametric statistical method,...
Abstract Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed phase II multicenter study of enzalutamide CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving Patients Methods: Eligible with underwent baseline metastasis biopsy then initiated 160 mg daily. A repeat was obtained at...
Abstract Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene play an important role oncogenesis; other they are thought to be passenger events. Although regulatory element and copy number alterations resulting these structural variants known lead transcriptional dysregulation across cancers, the extent which events functional dependencies with impact on cell survival is variable. Here we used CRISPR-Cas9 dependency screens evaluate fitness of 3,277...
Poison frogs acquire chemical defenses from the environment for protection against potential predators. These defensive chemicals are lipophilic alkaloids that sequestered by poison dietary arthropods and stored in skin glands. Despite decades of research focusing on identifying frog alkaloids, we know relatively little about how environmental variation subsequent arthropod availability impacts alkaloid loads frogs. We investigated seasonal influences profiles through changes diet Climbing...
Molecular profiling studies have enabled discoveries for metastatic prostate cancer (MPC) but predominantly occurred in academic medical institutions and involved non-representative patient populations. We established the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to involve patients with MPC living anywhere US Canada molecular research. Here, we present results from our partnership first 706 MPCproject participants. While 41% of partners...
The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis SVs across histological genomic subtypes, we identified distinct global properties between subtypes. These included the frequency size SV classes, their relation to chromothripsis events, role topologically associated domain (TAD) boundary altering on cancer-related genes. Following our prior identification double-stranded break repair deficiency a...
ABSTRACT Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, nearly universal. Other treatment modalities, immune checkpoint inhibitors, have provided minimal benefit except in rare subsets patients 1,2 . Both tumour...
Abstract Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes a range human NECs show convergence to activation common epigenetic program. With particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), analyzed cell lines, patient-derived xenograft (PDX) models samples existence two distinct NEPC...
Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). synthesis of GSH non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). imbalance implicated in many diseases, but requirement for adult tissues unclear. To interrogate this, we developed a series
Article Tools CASE REPORTS OPTIONS & TOOLS Export Citation Track Add To Favorites Rights Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/PO.22.00183 JCO Precision Oncology no. 6 (2022) e2200183. Published online September 8, 2022. PMID: 36075011 Mutational Footprint of Platinum Chemotherapy in a Secondary Thyroid Cancer Julia Schiantarelli , BS1,2xJulia SchiantarelliSearch for by this author; Theodora Pappa, MD, PhD1,2,3xTheodora PappaSearch Jake Conway...
Pediatric solid tumors are rare malignancies that represent a leading cause of death by disease among children in developed countries. The early age-of-onset these suggests germline genetic factors involved, yet conventional testing for short coding variants established predisposition genes only identifies pathogenic events 10-15% patients. Here, we examined the role structural (SVs)-an underexplored form variation-in pediatric extracranial using genome sequencing 1,766 affected children,...
Abstract Background: Poly-(adenosine diphosphate ribose) polymerase (PARP) inhibitors have demonstrated efficacy in patients with platinum-sensitive pancreatic cancer who harbor germline BRCA 1/2 pathogenic variants (PVs). Whether PARP are effective a broader population of is still under investigation. Methods: This was multicenter, single arm, open-label phase II trial (NCT03601923) investigating the use inhibitor niraparib advanced cancer. Eligible were required to or somatic mutations...
The extent to which clinical and genomic characteristics associate with prostate cancer clonal architecture, tumor evolution, therapeutic response remains unclear. Here, we reconstructed the architecture evolutionary trajectories of 845 tumors harmonized molecular data. We observed that from patients who self-reported as Black had more linear monoclonal architectures, despite these men having higher rates biochemical recurrence. This finding contrasts prior observations relating polyclonal...
Abstract Poison frogs acquire chemical defenses from the environment for protection against potential predators. These defensive chemicals are lipophilic alkaloid toxins that sequestered by poison dietary arthropods and stored in skin glands. Despite decades of research focusing on identifying frog toxins, we know relatively little about how environmental variation subsequent arthropod availability impacts toxicity frogs. We investigated seasonal influences toxin profiles through changes...
ABSTRACT High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and cancer-specific mortality 1 . Recent clinical trials have shown that intensifying anti-androgen therapies administered prior to prostatectomy can induce pathologic complete responses (pCR) or minimal residual disease (MRD) (<5 mm), together termed exceptional response, although the molecular determinants these outcomes are largely unknown. Here, we performed whole exome (WES)...
ABSTRACT Molecular profiling studies have enabled numerous discoveries for metastatic prostate cancer (MPC), but they mostly occurred in academic medical institutions focused on select patient populations. We developed the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org ), a patient-partnered initiative to empower MPC patients living anywhere U.S. and Canada participate molecular research contribute directly translational discovery. Here we present clinicogenomic results from...