Gad Getz

Gad Getz
Broad Institute of MIT and Harvard · Cancer Program

About

912
Publications
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199,244
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Publications

Publications (912)
Article
Full-text available
Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrate 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clusterin...
Article
The introduction of checkpoint blockade therapy, specifically anti-PD-1/PD-L1 agents, has transformed the treatment landscape of advanced Non-Small Cell Lung Cancer (NSCLC). While our understanding of the biology underlying immunotherapy in NSCLC is still incomplete, studies to date have established central roles for Tumor Mutation Burden (TMB) and...
Article
Lung adenocarcinoma (LUAD) is one of the most common cancer types with various available treatment modalities. However, better biomarkers of response are still needed for further improving precision medicine. Therefore, a robust LUAD subtyping can substantially aid in determining the most effective therapies that target subtype-specific vulnerabili...
Article
Introduction: Multiple myeloma (MM) is consistently preceded by two precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). The distinctions between MGUS, SMM, and MM rely on clinical values with inherent variation relating to tumor burden quantified from bone marrow biopsies, a measure...
Article
Emerging classifiers that leverage recent advances in the characterization of mutational signatures have identified a broader range of cancer patients with DNA repair deficiencies, many of whom do not harbor mutations or epigenetic silencing of canonical DNA repair genes. Investigating the various mechanisms underlying dysfunctional DNA damage resp...
Article
Background: Multiple Myeloma (MM) is a hematological malignancy characterized by abnormal proliferation of terminally differentiated plasma cells (PCs) in the bone marrow (BM). MM is almost always preceded by the precursor stage smoldering multiple myeloma (SMM). BM biopsies are useful to monitor disease progression, but they are invasive and not r...
Article
Chimeric Antigen Receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B-cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment, across the commercially available CAR-T products with differing designs. Known failure mechanisms such as an...
Article
We studied resistance mechanisms to hormone therapy and CDK4/6 cell cycle inhibitors in ER+ breast cancer by analyzing whole-exome, whole-genome, single-cell, and bulk transcriptomes in 120 autopsy samples from 13 patients obtained by the Massachusetts General Hospital Rapid Autopsy program. For each patient, we inferred the clonal structure of the...
Article
Introduction: Multiple myeloma (MM) develops from indolent stages monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Precursor conditions are incidentally diagnosed and require invasive bone marrow (BM) biopsies for complete characterization, highlighting the urgent need for improved early detection met...
Article
Detecting cancer at early stages or upon recurrence is critical to decreasing cancer morbidity and mortality. We developed TuFEst (Tumor Fraction Estimator), a cost-effective computational approach for pan-cancer detection and tumor burden estimation from ultra-low coverage whole genome sequencing (~0.1x, ULP-WGS) of minimally invasive cell-free DN...
Article
Richter’s syndrome (RS) arising from chronic lymphocytic leukemia (CLL) is a striking example of an aggressive malignant histology that emerges from indolent cancer. RS is a major barrier to disease control in CLL and is associated with poor clinical outcomes and limited survival. The genetic basis of RS is poorly understood, and its relationship t...
Article
Introduction: Patients with hematological malignancies exhibit inferior response to SARS-CoV2 vaccination, compared to healthy individuals, however little is known about patients with precursor hematological malignancies and the cellular underpinnings of vaccination response. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering...
Article
Protein complexes are sets of proteins that not only physically interact with each other, but also play important roles in progression of diseases like cancer. However, little is known about the co-regulation patterns of complexes and how many of them could be potential therapeutic targets. We collected 16,680 complexes from CORUM, Reactome, Comple...
Article
Premalignant tissue samples collected at different timepoints along the path to invasive tumors have been used to establish the typical order of somatic genetic events in several cancer types. For many other cancer types, however, precancer tissue is unobtainable, leaving the genetic progression unknown. Here, we demonstrate an approach that can re...
Article
Hemangioblastomas (HBs) are highly vascular tumors of the Central Nervous System that are commonly associated with the familial von Hippel-Lindau (VHL) disease and contribute significantly to the morbidity and mortality of VHL patients. They are characterized by high heterogeneity but the cell origin of HB tumors is still unclear, and the genomic l...
Article
1058 Background: Patients (pts) with HR+ HER2- ABC ultimately develop endocrine resistance. To gain insights into the genetic mechanisms of resistance we performed WES on serial plasma samples from endocrine resistant pts treated on a clinical trial (NCT02448771). Methods: Plasma samples were collected at baseline (n=36), day 1 of cycle 2 (n=33), a...
Article
e21178 Background: ICIs are cornerstones of therapy for advanced NSCLC. Despite dramatic and sometimes durable responses to therapy, most patients (pts) either (i) do not respond to therapy (intrinsic resistance), or (ii) subsequently progress after initial clinical benefit (acquired resistance). Currently, insights into the molecular mechanisms of...
Article
Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profil...
Article
Full-text available
Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies1–6, but it has shown limited efficacy against solid tumours. Solid tumours may have cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manne...
Preprint
Chimeric Antigen Receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B-cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain novel insights into the basi...
Article
In chronic lymphocytic leukemia (CLL), B-cell receptor signaling, tumor-microenvironment interactions and somatic mutations drive disease progression. To better understand the intersection between the microenvironment and molecular events in CLL pathogenesis, we integrated bulk transcriptome profiling of paired peripheral blood (PB) and lymph node...
Preprint
Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). While our understanding of the biology underlying immune checkpoint blockade in NSCLC is still incomplete, studies to date have established predictive roles for PD-L1 tumor expression and tumor mutational burden (TMB). To expand our under...
Article
Full-text available
The imminent release of tissue atlases combining multichannel microscopy with single-cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards to guide data deposition, curation and release. We describe a Minimum Information about Highly Multiplexed Tissue Imaging (MITI) standard...
Article
Background Prevalence estimates for monoclonal gammopathy of undetermined significance (MGUS) are based on predominantly White study populations screened by serum protein electrophoresis supplemented with immunofixation electrophoresis. A prevalence of 3% is reported for MGUS in the general population of European ancestry aged 50 years or older. MG...
Preprint
Lung adenocarcinoma is one of the most common cancer types with various treatment modalities. However, better biomarkers to predict therapeutic response are still needed to improve precision medicine. We utilized a consensus hierarchical clustering approach on 509 LUAD cases from TCGA to identify five robust LUAD expression subtypes. We then integr...
Article
Tamoxifen is widely used in the adjuvant treatment of estrogen receptor–positive (ER+) breast cancer and is an important drug for pre-menopausal women and post-menopausal patients who cannot tolerate aromatase inhibitors. Despite the clear clinical benefit in improving relapse-free and overall survival in these patients, an adverse effect of tamoxi...
Preprint
Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk sequencing technologies. Here, we generated and analyzed single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 h...
Article
Full-text available
Tumor-associated epitopes presented on MHC-I that can activate the immune system against cancer cells are typically identified from annotated protein-coding regions of the genome, but whether peptides originating from novel or unannotated open reading frames (nuORFs) can contribute to antitumor immune responses remains unclear. Here we show that pe...
Article
Full-text available
Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains unde...
Article
Multiple myeloma (MM) is a haematological malignancy of plasma cells characterized by substantial intraclonal genetic heterogeneity. Although therapeutic advances made in the past few years have led to improved outcomes and longer survival, MM remains largely incurable. Over the past decade, genomic analyses of patient samples have demonstrated tha...
Article
Full-text available
Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify dige...
Article
Background: Recent studies have identified clinical and genomic factors contributing to worse clinical outcomes in patients with multiple myeloma (MM). Clonal hematopoiesis (CH) reflects the presence of somatic driver mutations in the blood or marrow of otherwise asymptomatic individuals. Using a variant allele frequency (VAF) cutoff of 2%, we rece...
Article
Introduction: Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by the abnormal growth of clonal plasma cells in the bone marrow (BM). In most cases MM develops from early, asymptomatic disease stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Despite effective...
Article
Introduction: Multiple Myeloma (MM) is an incurable plasma cell malignancy commonly preceded by the asymptomatic stage smoldering multiple myeloma (SMM). MM is characterized with significant genomic heterogeneity of chromosomal gains and losses (CNVs), translocations, and point mutations (SNVs); alterations that are also observed in SMM patients. H...
Article
Background Multiple myeloma (MM) evolves from monoclonal gammopathy of undetermined significance (MGUS), a clinically detectable but asymptomatic premalignant phase seen in ~3% of the general population 50 years of age or older. The prevalence of MGUS has not been described in a population at high risk of developing MM, specifically Black/African A...
Article
Our understanding of disease progression in multiple myeloma (MM) and its precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), is classically founded on bulk analysis studies. Low disease burden at the precursor stages has precluded comprehensive analyses of the transcriptomic events...
Article
Background Patients with Smoldering Multiple Myeloma (SMM) are typically observed until progression to overt Multiple Myeloma (MM), but early treatment of high-risk patients may improve outcomes. Clinical and genomic biomarkers can help to identify SMM patients at high risk of progression, but whether parallel profiling of the tumor immune microenv...
Article
Background Chimeric Antigen Receptor (CAR) therapy has had a transformative impact on the treatment of hematologic malignancies 1–6 but success in solid tumors remains elusive. We hypothesized solid tumors have cell-intrinsic resistance mechanisms to CAR T-cell cytotoxicity. Methods To systematically identify resistance pathways, we conducted a ge...
Article
Background Patients with Smoldering Multiple Myeloma (SMM) are typically observed until progression, but early treatment of high-risk patients may improve outcomes. Clinical and genomic biomarkers can be used to identify SMM patients at high risk of progression, however parallel profiling of the tumor immune microenvironment (TIME) may further impr...
Article
Full-text available
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...
Article
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphopr...
Article
Sacituzumab Govitecan (SG), the first antibody drug conjugate (ADC) approved for triple-negative breast cancer (TNBC), incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pre-treatment and post-progression spec...
Article
Full-text available
Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing t...
Preprint
Full-text available
Understanding the function of genes and their regulation in tissue homeostasis and disease requires knowing the cellular context in which genes are expressed in tissues across the body. Single cell genomics allows the generation of detailed cellular atlases in human tissues, but most efforts are focused on single tissue types. Here, we establish a...
Article
Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also iden...
Preprint
Cancer immunotherapy with checkpoint blockade (CPB) leads to improved outcomes in melanoma and other tumor types, but a majority of patients do not respond. High tumor mutation burden (TMB) and high levels of tumor-infiltrating T cells have been associated with response to immunotherapy, but integrative models to predict clinical benefit using DNA...
Conference Paper
p>Mechanisms of resistance to venetoclax, a highly selective oral BCL2 inhibitor approved for therapy of CLL, remain poorly understood and we sought to characterize the clonal evolution of resistance in patients developing progressive disease on venetoclax. We performed whole-exome sequencing (WES) on 7 relapsed/refractory CLL patients with disease...
Conference Paper
p>The advent of PD-1/PD-L1 agents has transformed the therapeutic landscape of many advanced cancers, including non-small cell lung cancer (NSCLC). However, our understanding of the genomic biomarkers underlying effective treatment response remain limited. Here we provide updated results from our ongoing effort, the Stand Up To Cancer Lung (SU2C-Lu...
Article
Full-text available
Lineage-tracing methods have enabled characterization of clonal dynamics in complex populations, but generally lack the ability to integrate genomic, epigenomic and transcriptomic measurements with live-cell manipulation of specific clones of interest. We developed a functionalized lineage-tracing system, ClonMapper, which integrates DNA barcoding...
Article
While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chron...
Article
Single-cell RNA sequencing identifies an inflammatory subpopulation of mesenchymal stromal cells in patients with multiple myeloma.
Preprint
Full-text available
A lymphocyte suffers many threats to its genome, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse microenvironments. After developing protocols for single-cell lymphocyte expansions, we sequenced whole genomes from 717 normal naive and memory B and T lymphocytes and hematopoietic stem cells...
Article
Full-text available
Natural mitochondrial DNA (mtDNA) mutations enable the inference of clonal relationships among cells. mtDNA can be profiled along with measures of cell state, but has not yet been combined with the massively parallel approaches needed to tackle the complexity of human tissue. Here, we introduce a high-throughput, droplet-based mitochondrial single-...
Article
Full-text available
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all...
Preprint
Full-text available
Complex chromosomal alterations are a hallmark of advanced cancers but rarely seen in normal tissue. The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations that can drive their transformation through focal oncogenic amplifications. However, the etiology and evolution dynamics o...
Article
Full-text available
Inhibitors of Bruton's tyrosine kinase (BTKi) and phosphatidylinositol 3-kinase delta (PI3Kδi) that target the B cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While mutations associated with resistance to BTK inhibitors have been identified, limited data are available on mechanisms of...
Article
Post-sequencing quality control is a crucial component of RNA sequencing (RNA-seq) data generation and analysis, as sample quality can be affected by sample storage, extraction, and sequencing protocols. RNA-seq is increasingly applied to cohorts ranging from hundreds to tens of thousands of samples in size, but existing tools do not readily scale...
Article
Single-cell RNA-sequencing can help in the prediction of drug resistance in patients with multiple myeloma.
Article
Full-text available
A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01185-6.
Article
Full-text available
RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(−) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+)...
Preprint
Full-text available
Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit child...
Preprint
Full-text available
Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor e...
Article
Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel...