Oncogenomics Laboratoryat the Moores Cancer Center

Research


Our research program is focused on the identification of genetic and epigenetic markers for cancer prevention, progression as well as drug response to support the development of personalized cancer care. Below are a few examples of our most current research.

Ultra Deep Targeted Sequencing for cancer care

The detection of somatic mutations in clinical tumor samples is challenging. Indeed, in addition to malignant cells, tumor samples are frequently composed of stroma, normal cells or immune cells. Traditional assays only look at a few mutations (1-40) and are not sensitive to detect mutations at low allelic fractions, in a subset of the cells. On the other hand, the use of broad high throughput sequencing (whole genomes or whole exomes) is not always justified (lack of clinical utility for most genes) and is generally limited to the detection of mutations at high allelic fraction, present in most cells. In order to increase the utility of such molecular profiling, we developed the UDT-Seq assay, combining microdroplet PCR and High Throughput sequencing. We can sequence up to 1500 amplicons at an average coverage >1000x and are able to detect 95% of the mutations present at 5% or more, with minimal false positive. This assay is focused on the most actionable cancer genes and is streamlined for clinical use. We developed a dedicated analysis pipeline, Mutascope, which is specifically optimized for the detection of mutations at low allelic fraction from PCR amplicons data. We have demonstrated that the specific features of UDT-Seq (inclusion of germline DNA, inference of copy number alterations, and detection of mutation at low allelic fraction) can help identify more actionable events in more patients, for a potential increased clinical benefit.

Collaborators: Richard Schwab, Kelly Frazer, Lisa Madlensky, Hoda Anton-Culver

Cancer Mutational Profiling

The Cancer Genome Atlas is providing an unprecedented resource of molecular profiles in multiple cancer types. However there are still many instances where a generic cancer mutational profile is not sufficient to understand more specific aspects of the disease biology especially in rare cancers. In collaboration with other investigators, we are studying the somatic mutations that occur in rare cancers (mucinous appendix cancer, peritoneal mesothelioma), mouse cancer models of hepatocellular carcinoma, myelodisplastic syndromes or gastro-intestinal stromal tumors. Importantly, and in contrast to publically available datasets, the quality of the clinical information and phenotypic characterization of the samples we study greatly improves the translational relevance of the questions that can be addressed using genome-wide methods. The goal of this research is to advance our understanding of cancer progression and identify potential targets for therapy.

Collaborators: Michael Karin, Andrew Lowy, Rafael Bejar, Kelly Frazer, Jason Sicklick, Karen Messer

Genome-wide Location of DNA adducts

DNA adducts are the hallmark and most common form of DNA damage in the cell. They result from environmental carcinogen exposure (such as UV) or during chemotherapy using DNA modifying agents like cisplatin (cDDP) or alkylators such as chlorambucil (CLB). While mechanisms underlying sensitivity, agent homeostasis, detoxification, DNA repair and apoptosis, have been well investigated, the central molecular event, the formation of adducts, is not well understood in vivo. Evidence suggests that the epigenetic landscape and the structure of the chromatin influences the formation of adducts and mediates drug sensitivity. We are therefore developing a molecular assay that allows the genome-wide identification of the location of DNA adducts in vivo. With such a method, we will be able to study directly the interactions between DNA damage and chromatin as well as to provide a more precise and comprehensive description of the mechanism of DNA damage and repair in vivo in various cells and cancer types. The long-term benefits of such research include the prediction of drug sensitivity or the study of epigenetic modifying compounds to rationalize combinations for optimal drug efficacy.

Collaborator: Stephen Howell, MD

HIPAA-compliant cloud computing for cancer genomics

Genetic information is considered protected health information (PHI) and as a oconsequence the highest security standards need to be applied for its storage, analysis and sharing. The oncogenomics labroatory is using state of the art iDASH compute cloud for its main computation. As a consequence, we participate in the development of optimal workflows and virtual machines for the analysis of patient-derived genomic datasets such as whole exomes, whole genomes, RNA-seq or genotyping arrays. The laboratory also participates in the deployment of external read alignment and variant calling workflows to assist the ICGC PanCancer Analysis Workgroup.

Collaborators: Lucila Ohno-Machado, Claudiu Farcas, Antonios Koures, Jihoon Kim



In addition to the collaborators mentioned above, the Oncogenomics laboratory works closely with the UC San Diego Institute for Genomic Medicine Genomics Center to generate high throughput sequencing data and develop novel assays and protocols.

Our research is supported by funding from NCI IMAT program, UCSD Clinical and Translational Research Institute, The Moores Cancer Center and NHLBI.



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