A5051755724- Cancer Genomics and Diagnostics
- Bioinformatics and Genomic Networks
- Genetics, Bioinformatics, and Biomedical Research
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- BRCA gene mutations in cancer
- Click Chemistry and Applications
- Cutaneous Melanoma Detection and Management
- bioluminescence and chemiluminescence research
- CRISPR and Genetic Engineering
- SARS-CoV-2 and COVID-19 Research
- Prostate Cancer Diagnosis and Treatment
- Single-cell and spatial transcriptomics
- Cholinesterase and Neurodegenerative Diseases
- Prostate Cancer Treatment and Research
- Ferroptosis and cancer prognosis
- Genomics and Rare Diseases
- Melanoma and MAPK Pathways
- PI3K/AKT/mTOR signaling in cancer
- interferon and immune responses
- Evolution and Genetic Dynamics
- Computational Drug Discovery Methods
- Gene expression and cancer classification
Broad Institute
2018-2025
Dana-Farber Cancer Institute
2018-2025
Harvard University
2017-2024
Critical Path Institute
2022-2023
Massachusetts Institute of Technology
2018-2023
PathAI (United States)
2022-2023
Health First
2023
Dana-Farber Brigham Cancer Center
2023
Brigham and Women's Hospital
2023
Abstract Motivation Venn and Euler diagrams are a popular yet inadequate solution for quantitative visualization of set intersections. A scalable alternative to visualizing intersecting sets their properties is needed. Results We developed UpSetR, an open source R package that employs matrix-based show intersections sets, size, other properties. Availability implementation UpSetR available at https://github.com/hms-dbmi/UpSetR/ released under the MIT License. Shiny app...
Abstract Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort patients with melanoma ( n = 144) treated ICB, whole-exome and whole-transcriptome sequencing pre-treatment tumors. We found that mutational burden as predictor response was confounded by subtype, whereas multiple novel genomic transcriptomic features predicted...
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens a data-mining approach to identify drugs that can upregulate without inducing PD-L1. screening identified TRAF3, suppressor of the NFκB pathway, as negative regulator not The Traf3-knockout gene signature is associated better survival in ICB-naïve and ICB response. We then screened for similar...
Abstract Venn and Euler diagrams are a popular yet inadequate solution for quantitative visualization of set intersections. A scalable alternative to visualizing intersecting sets their properties is needed. We developed UpSetR, an open source R package that employs matrix-based show intersections sets, size, other properties. UpSetR available at https://cran.r-project.org/package=UpSetR released under the MIT License. Shiny app https://gehlenborglab.shinyapps.io/upsetr/ .
<h3>Importance</h3> Less than 10% of patients with cancer have detectable pathogenic germline alterations, which may be partially due to incomplete variant detection. <h3>Objective</h3> To evaluate if deep learning approaches identify more variants in cancer. <h3>Design, Setting, and Participants</h3> A cross-sectional study a standard detection method 2 convenience cohorts prostate melanoma enrolled the US Europe between 2010 2017. The final date clinical data collection was December...
We report results from a phase II study assessing the efficacy of WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC).Patients mTNBC treated 0-1 prior lines chemotherapy received 75 mg/m2 i.v. followed 21 days later by plus 200 mg oral twice daily for five doses every days. The had 90% power to detect difference between null (20%) and alternative (40%) objective response rates (ORR) one-sided type I error 0.1: an ORR >30% was predefined as making...
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 Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results ( n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ cancer, computationally dissect genomic and/or transcriptomic data pre-treatment tumors 52) molecular associations efficacy, and identify cytokine changes differentiating response ICI-related toxicity 58). Despite no...
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...
Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease globally and a leading cause for transplantation in US. Its pathogenesis remains imprecisely defined. We combined two high-resolution modalities to tissue samples from NASH clinical trials, machine learning (ML)-based quantification of histological features transcriptomics, identify genes that are associated with progression events. A histopathology-driven 5-gene expression signature predicted events patients F3...
Abstract Tumor molecular profiling of single gene-variant (‘first-order’) genomic alterations informs potential therapeutic approaches. Interactions between such first-order events and global features (for example, mutational signatures) are increasingly associated with clinical outcomes, but these ‘second-order’ not yet accounted for in interpretation algorithms knowledge bases. We introduce the Molecular Oncology Almanac (MOAlmanac), a paired algorithm base to enable integrative multimodal...
We have previously shown that non-cytotoxic concentrations (600-1200 U/ml) of recombinant mouse tumour necrosis factor-alpha (TNF-alpha) can induce differentiation a subclone (JCS) the WEHI-3B myelomonocytic leukaemia cell line into mature cells with characteristics macrophages. In present study, effects interleukin-4 (IL-4), either alone or in combination TNF-alpha, on growth and JCS were examined. IL-4 (20-5000 inhibited dose-dependent manner but did not differentiation. However,...
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...
An amendment to this paper has been published and can be accessed via a link at the top of paper.
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 The biological role of PBRM1 loss-of-function (LOF) mutations mediating response to immune checkpoint blockade (ICB) in clear cell renal carcinoma (ccRCC) remains an area active investigation. A recent study (hereafter, ‘the MSK study’) evaluated this hypothesis a clinically heterogeneous single institution retrospective ccRCC cohort using targeted sequencing and did not find univariable statistically significant association for LOF time-to-treatment failure (TTF), but report...
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...
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 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)...