Dale W. Garsed
A5078379854- Ovarian cancer diagnosis and treatment
- Cancer Genomics and Diagnostics
- PARP inhibition in cancer therapy
- Cancer-related molecular mechanisms research
- RNA modifications and cancer
- Ferroptosis and cancer prognosis
- CRISPR and Genetic Engineering
- Epigenetics and DNA Methylation
- Virus-based gene therapy research
- Endometrial and Cervical Cancer Treatments
- DNA Repair Mechanisms
- Cancer Immunotherapy and Biomarkers
- Immune cells in cancer
- Renal cell carcinoma treatment
- Genomics and Chromatin Dynamics
- Reproductive System and Pregnancy
- Genomics and Phylogenetic Studies
- Evolution and Genetic Dynamics
- RNA and protein synthesis mechanisms
- Chromosomal and Genetic Variations
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Bioinformatics and Genomic Networks
- Genetic factors in colorectal cancer
- Genomic variations and chromosomal abnormalities
Peter MacCallum Cancer Centre
2014-2025
The University of Melbourne
2014-2025
Royal Women's Hospital
2015
Ian Potter Foundation
2009
Cancer develops through a process of somatic evolution
Abstract A key mutational process in cancer is structural variation, which rearrangements delete, amplify or reorder genomic segments that range size from kilobases to whole chromosomes 1–7 . Here we develop methods group, classify and describe somatic variants, using data the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium International Cancer Genome (ICGC) The Atlas (TCGA), aggregated whole-genome sequencing 2,658 cancers across 38 tumour types 8 Sixteen signatures variation...
Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies selected types have suggested chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium International Cancer Genome (ICGC) The Atlas (TCGA), we analyze patterns across 2,658 tumors 38 using whole-genome sequencing We find...
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, drivers ITH across cancer types are poorly understood. To address this, we extensively characterize whole-genome sequences 2,658 samples spanning 38 types. Nearly all informative (95.1%) contain evidence distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection driver mutations most...
Abstract About half of all cancers have somatic integrations retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms retrotransposition 2,954 cancer genomes from 38 histological subtypes within framework Pan-Cancer Analysis Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired events, which affected 35% samples spanned a range event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as first...
Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, boundaries separating different have important roles in reinforcing stability of these features. Indeed, domain disruptions human cancers can lead misregulation gene expression. However, frequency remains unclear. Here, as part Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium International...
Abstract Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for resource lncRNAs with validated roles. Furthermore, it remains debated whether mutated can drive tumorigenesis, and such functions could be conserved during evolution. Here, as part ICGC/TCGA Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium, we introduce Cancer LncRNA Census (CLC), compilation 122 GENCODE causal roles in phenotypes. In contrast to existing databases, CLC requires...
Multi-omics datasets represent distinct aspects of the central dogma molecular biology. Such high-dimensional profiles pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple using statistical fusion, rationalizes contributing evidence highlights associated genes. As part ICGC/TCGA Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing from...
Abstract Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative lengthening associated with ATRX DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium , we dissect whole-genome sequencing data over 2500 matched tumor-control samples from 36 different tumor types aggregated within to characterize genomic footprints these mechanisms. While content tumors mutations...
Abstract The catalog of cancer driver mutations in protein-coding genes has greatly expanded the past decade. However, non-coding are less well-characterized and only a handful recurrent mutations, most notably TERT promoter have been reported. Here, as part ICGC/TCGA Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 across 38 tumor types, we perform multi-faceted pathway network analyses 2583 genomes 27 types compiled by PCAWG...
Abstract Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, subset of patients has an unexpected dramatic and durable response to treatment. We sought identify clinical, pathological, molecular determinants exceptional survival in women high-grade serous (HGSC), disease associated the majority deaths. Experimental Design: evaluated histories 2,283 and, after applying stringent clinical pathological selection criteria, identified 96 HGSC that represented...
Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and molecularly characterized by RAS pathway activation. Using exome whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX NF1, USP9X, KRAS, BRAF, NRAS were mutually exclusive; however, found significant co-occurrence of Missense clustered at N-terminus region its role ensuring initiation fidelity. Coexpression mutant proteins promoted...
Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are strongest risk factors for developing osteosarcoma. Recapitulating human predisposition, we found that Rb1+/– mice exhibited accelerated development of IR-induced osteosarcoma, with a latency 39 weeks. Initial exposure osteoblasts to carcinogenic doses IR vitro vivo induced RB1-dependent senescence expression panel proteins known as senescence-associated secretory phenotype (SASP), dominated...
Abstract We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines allele frequencies both SV breakends, then simultaneously estimates and copy number. assess performance using in silico mixtures real samples, at known proportions, created two clonal metastases same patient. find that SVclone’s is comparable to single-nucleotide variant-based methods, despite having...
Abstract The discovery of driver mutations is one the key motivations for cancer genome sequencing. Here , as part ICGC/TCGA Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium which aggregated whole sequencing data from 2658 cancers across 38 tumour types, we describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify in coding non-coding sites within genomes. Using total 1373 genomic features derived public sources, DriverPower’s...
Abstract The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types co-occur in the same tumours. However, it remains unclear how processes change during evolution due to lack reliable methods reconstruct evolutionary trajectories mutational signature activity. Here, as part ICGC/TCGA Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658...
Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis biopsies from 45 patients, 9 Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) 36 FIGO III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 ligands, collagen structure...
Abstract We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning broad spectrum purity. identified patients with longer progression-free survival had increased immune-related signatures validated proteins correlating tumor-infiltrating lymphocytes in 65 tumors an independent cohort HGSOC patients, as well overall additional 126 patient cohort. that homologous...
Abstract Purpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes observed in a subset of patients. The explanation for this is unknown but may be due misclassification high-grade serous cancer (HGSOC) as OCCC or mixed histology. Experimental Design: To discover potential biomarkers survival benefit following we ascertained cohort 68 Japanese and Australian patients whom progression-free (PFS) overall (OS) could...