A5004909914- Melanoma and MAPK Pathways
- Cancer Genomics and Diagnostics
- Cancer Research and Treatments
- Mechanisms of cancer metastasis
- Genomic variations and chromosomal abnormalities
- Genomics and Phylogenetic Studies
- Chromosomal and Genetic Variations
- Glioma Diagnosis and Treatment
- interferon and immune responses
- CRISPR and Genetic Engineering
- SARS-CoV-2 and COVID-19 Research
- Epigenetics and DNA Methylation
- Cancer Cells and Metastasis
- Mosquito-borne diseases and control
- Cancer-related Molecular Pathways
- Advanced biosensing and bioanalysis techniques
- RNA Research and Splicing
- Vector-Borne Animal Diseases
- Genomics and Chromatin Dynamics
- Viral Infections and Vectors
- Cancer-related molecular mechanisms research
- Protein Degradation and Inhibitors
- Gene expression and cancer classification
- COVID-19 Clinical Research Studies
University of California, San Diego
2020-2025
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...
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...
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 whole genome karyotype refers to the sequence of large chromosomal segments that make up an individual's genotype. analysis, which includes descriptions aneuploidies and other rearrangements is crucial for understanding genetic risk factors, diagnosis, treatment decisions, counseling linked constitutional disorders. current karyotyping standard based on microscopic examination chromosomes, a complex process requires high expertise offers Mb scale resolution. Optical Genome Mapping (OGM)...
Impressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural (SVs), which account for a substantial proportion genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely ill patients identify rare/unique SVs as decisive predisposition factors...
Abstract Oncogene amplification is a key driver of cancer pathogenesis. Both breakage fusion bridge (BFB) cycles and extrachromosomal DNA (ecDNA) can lead to high oncogene copy numbers, but the impact BFB amplifications on intratumoral heterogeneity, treatment response, patient survival remains poorly understood due detection challenges with sequencing. We introduce an algorithm, OM2BFB, designed detect reconstruct using optical genome mapping (OGM). OM2BFB demonstrates precision (>93%)...
Optical mapping (OM) provides single-molecule readouts of fluorescently labeled sequence motifs on long fragments DNA, resolved to nucleotide-level coordinates. With the advent microfluidic technologies for analysis DNA molecules, it is possible inexpensively generate OM data (>150 kbp) at high coverage. In addition scaffolding de novo assembly, can be aligned a reference genome identification genomic structural variants. We introduce FaNDOM (Fast Nested Distance Seeding Maps)—an optical map...
SUMMARY Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but landscape its association with specific MB subgroups, impact on potential clinical implications, are not known. We assembled a retrospective cohort 468...
ABSTRACT Extrachromosomal DNA (ecDNA) is a common mode of oncogene amplification but challenging to analyze. Here, we present method for targeted purification megabase-sized ecDNA by combining in-vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis agarose-entrapped genomic (CRISPR-CATCH). We demonstrate strong enrichment molecules containing EGFR , FGFR2 MYC from human cancer cells. Targeted versus chromosomal enabled phasing genetic variants provided definitive proof an...
SUMMARY Oncogene amplification is a major driver of cancer pathogenesis. Breakage fusion bridge (BFB) cycles, like extrachromosomal DNA (ecDNA), can lead to high copy numbers oncogenes, but their impact on intratumoral heterogeneity, treatment response, and patient survival are not well understood due difficulty in detecting them by sequencing. We describe novel algorithm that detects reconstructs BFB amplifications using optical genome maps (OGMs), called OM2BFB. OM2BFB showed precision...
Abstract Background The varied clinical manifestations and outcomes in patients with SARS-CoV-2 infections implicate a role of host-genetics the predisposition to disease severity. This is supported by evidence that now emerging, where initial reports identify common risk factors rare genetic variants associated high for severe/ life-threatening COVID-19. Impressive global efforts have focused on either identifying utilizing short-read sequencing data Genome-Wide Association Studies (GWAS)...
Abstract 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 mechanism driving 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. Here, we introduce powerful new computational method,...
Optical mapping provides single-molecule readouts of the locations fluorescently labeled sequence motifs on long fragments DNA, resolved to nucleotide-level coordinates. With advent microfluidic technologies for manipulating large numbers individual molecules, and advances in imaging fluorescent DNA tags, it is possible inexpensively generate high coverage OM molecules (>150Kbp). In addition its use scaffolding de novo assembly, optical map data can also be mapped a reference identifying...
<div>Abstract<p>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 <i>BRAF</i><sup>V600</sup> through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring...
Supplementary Figure from Plasticity of Extrachromosomal and Intrachromosomal <i>BRAF</i> Amplifications in Overcoming Targeted Therapy Dosage Challenges
Supplementary Figure from Plasticity of Extrachromosomal and Intrachromosomal <i>BRAF</i> Amplifications in Overcoming Targeted Therapy Dosage Challenges