Jens Luebeck
A5061386740- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- Cancer-related molecular mechanisms research
- Head and Neck Cancer Studies
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Melanoma and MAPK Pathways
- Genomics and Phylogenetic Studies
- Cancer Research and Treatments
- Molecular Biology Techniques and Applications
- Glioma Diagnosis and Treatment
- Genomics and Chromatin Dynamics
- Advanced biosensing and bioanalysis techniques
- Mechanisms of cancer metastasis
- Genomic variations and chromosomal abnormalities
- Single-cell and spatial transcriptomics
- Chromosomal and Genetic Variations
- Genetic factors in colorectal cancer
- Cancer Cells and Metastasis
- DNA Repair Mechanisms
- Bacteriophages and microbial interactions
- Genomics and Rare Diseases
- Esophageal Cancer Research and Treatment
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Viral-associated cancers and disorders
University of California, San Diego
2017-2025
UC San Diego Health System
2021
University of Washington
2017
Abstract Focal oncogene amplification and rearrangements drive tumor growth evolution in multiple cancer types. We present AmpliconArchitect (AA), a tool to reconstruct the fine structure of focally amplified regions using whole genome sequencing (WGS) validate it extensively on simulated real datasets, across wide range coverage copy numbers. Analysis AA-reconstructed amplicons pan-cancer dataset reveals many novel properties number amplifications cancer. These findings support model which...
Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- multi-base substitutions
Abstract Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, is associated with poor outcomes for patients cancer 1–6 . At present, it unclear whether ecDNA a later manifestation genomic instability, or can be an early event in transition from dysplasia cancer. Here, better understand development ecDNA, we analysed whole-genome sequencing (WGS) data oesophageal adenocarcinoma (EAC) Barrett’s oesophagus. These included 206...
Abstract Extrachromosomal DNA (ecDNA) is a common mode of oncogene amplification but challenging to analyze. Here, we adapt CRISPR-CATCH, in vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis agarose-entrapped genomic DNA, previously developed for bacterial chromosome segments, isolate megabase-sized human ecDNAs. We demonstrate strong enrichment ecDNA molecules containing EGFR , FGFR2 MYC from cancer cells NRAS metastatic melanoma with acquired therapeutic resistance. Targeted...
Abstract Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced metastatic cancers 1–4 , but whether they mechanistically linked is unknown. Here we show that missegregation mitotic chromosomes, their sequestration in micronuclei 5,6 subsequent rupture the micronuclear envelope 7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans mice, as well cancer non-transformed cells. Some changes PTMs occur...
Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer
Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary copy number (fCNA) - enabling gene rapid tumor evolution, and rewiring regulatory circuitry. Resolving an fCNA's structure first step in deciphering mechanisms its genesis subsequent biological consequences. We introduce computational method, AmpliconReconstructor (AR), for integrating optical...
The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while different chromosomes assort independently
Abstract Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival 1–7 . At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription–replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses reveal pervasive RNA associated single-stranded DNA,...
To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal 8,060 newly diagnosed primary cancers, untreated metastases heavily pretreated tumors. The ecDNAs were at significantly higher frequency metastatic tumors compared to cancers. Tumors from chemotherapy-pretreated patients showed ecDNA In particular, tubulin inhibition associated with increases, suggesting a for treatment response. longitudinally matched tumor samples,...
Extrachromosomal DNA (ecDNA) presents a promising target for cancer therapy; however, its spatial-temporal diversity and influence on tumor evolution the immune microenvironment remain largely unclear. We apply computational methods to analyze ecDNA from whole-genome sequencing data of 595 urothelial carcinoma (UC) patients. demonstrate that drives clonal through structural rearrangements during malignant transformation recurrence UC. This supports model wherein tumors evolve via selective...
Focal amplifications (FA) can mediate targeted therapy resistance in cancer. Understanding the structure and dynamics of FAs is critical for designing treatments that overcome plasticity-mediated resistance. We developed a melanoma model dual MAPK inhibitor (MAPKi) bears BRAFV600 through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring BRAFV600E displayed mode switching between DMs HSRs, from both de novo genetic...
Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution drug resistance and poor outcomes. Applying computational methods for the detection reconstruction ecDNA across a retrospective cohort 481 medulloblastoma from 465 patients, we identify circular 82 patients (18%). Patients with ecDNA-positive were more than twice as likely to relapse three times die within 5 years diagnosis. A subset harbored multiple lineages, each...
The integration of viral sequences into the host genome is an important driver tumorigenesis in many mediated cancers, notably cervical cancer and hepatocellular carcinoma. We present ViFi, a computational method that combines phylogenetic methods with reference-based read mapping to detect integrations. In contrast read-based reference approaches, ViFi faster, shows high precision sensitivity on both simulated biological data, even when integrated virus novel strain or highly mutated....
Oncogene amplification is one of the most common drivers genetic events in cancer, potently promoting tumor development, growth, and progression. The recent discovery that oncogene commonly occurs on extrachromosomal DNA, driving intratumoral heterogeneity high copy number owing to its non-chromosomal mechanism inheritance, raises important questions about how subnuclear location amplified oncogenes mediates pathogenesis. Next-generation sequencing powerful but does not provide spatial...
In 2021, the World Health Organization reclassified glioblastoma, most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility transcription profiles clinical samples G4 IDHm astrocytomas were analyzed at single-cell resolution. These...
Abstract Oncogene amplification on extrachromosomal DNA (ecDNA) is a pervasive driver event in cancer, yet our understanding of how ecDNA forms limited. In this study, we couple CRISPR-based method for induction with extensive characterization newly formed ecDNAs to examine their biogenesis. We find that circularization efficient, irrespective 3D genome context, the formation 800 kb, 1 Mb, and 1.8 Mb reaching or exceeding 15%. show nonhomologous end joining microhomology-mediated both...
Focal gene amplifications are among the most common cancer-associated mutations1 but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy large (more than 1 Mbp) focal mediated by extrachromosomal DNAs (ecDNAs)2 spatiotemporally controlled manner mice. By coupling ecDNA formation with expression of selectable markers, track dynamics ecDNA-containing under physiological conditions presence specific selective pressures. We also apply...
Extrachromosomal DNA (ecDNA) is a central mechanism for focal oncogene amplification in cancer, occurring ∼15% of early-stage cancers and ∼30% late-stage cancers. ecDNAs drive tumor formation, evolution, drug resistance by dynamically modulating copy number rewiring gene-regulatory networks. Elucidating the genomic architecture ecDNA amplifications critical understanding pathology developing more effective therapies. Paired-end short-read (Illumina) sequencing mapping have been utilized to...