Research Activities

The division’s current research activities are highly collaborative and focused on two main areas of study: Characterization of Inherited Variants and Cancer Genomics.

Characterization of Inherited Variants

The Division of Genome Information Sciences is working closely with Dr. Christina Chambers in the National Children’s Study. This study will examine the effects

of the environment, as broadly defined to include factors such as air, water, diet, sound, family dynamics, community and cultural influences, and genetics on the growth, development, and health of children across the United States, following them from before birth until age 21 years. Drs. Frazer and Smith study whether ancestry, as estimated from high-throughput genetic data, can be effectively used as a surrogate for self-reported race and ethnicity. Their results will aid the ongoing study as they enroll 100,000 children throughout the United States.

Dr. Frazer and Dr. Harismendy have initiated and are leading investigators for a large NHLBI supported multi-disciplinary project in collaboration with Dr. Juan Carlos Izpisúa Belmonte, Dr. Neil Chi, Dr. Sylvia Evans, Dr. Lawrence Goldstein, Dr. Daniel O’Connor, Dr. Michael Rosenfeld, and Dr. Gene Yeo. The goal of the project is to use iPSC-derived cardiomyocytes from 225 genotyped individuals as cellular models to investigate how human genetic variation influences the gene regulatory networks involved in cardiac biology and disease.

In collaboration with Dr. John-Bjarne Hansen at the University of Tromsø (Norway), Drs. Frazer and Smith have generated whole-exome sequencing of 920 individuals and are analyzing these data to identify genetic risk factors for venous thromboembolism (VTE), a common disease with high recurrence rate, serious short- and long-term complications, and potential fatal outcome.

In collaboration with Dr. Stephen Spector, Drs. Frazer and Smith have generated whole-exome sequencing of 500 individuals and are analyzing these data to identify the host genetic factors associated with HIV-associated neurocognitive disorders (HAND) in children.

In collaboration with Dr. Joe Gleeson we are using advanced genomic technologies to address genetic mechanisms underlying human structural brain defects. The research goals are to identify new genes responsible for recessive structural brain defects in consanguineous families.

Cancer Genomics

Clinical sequencing at the Moores Cancer Center began in December of 2012 with the start of a personalized medicine program led by Dr. Kurzrock. Dr. Harismedy is assisting Dr. Kurzrock in interpretation of the clinical sequence data by participation in the weekly molecular tumor board.

In collaboration with Dr. Thomas Kipps at the UCSD Moores Cancer Center, Drs. Frazer and Smith are conducting a retrospective matched case-control study comparing an early-progressing group of chronic lymphocytic leukemia (CLL) patients with a later-progressing group. They have used genomic methods to identify changes in DNA mutations, epigenetic regulatory sites, and gene expression that occur as tumors become more aggressive during the progression of CLL.

Drs. Barrett and Frazer are developing the computational capabilities for using transcriptome sequencing data (RNA-seq) for the discovery of mRNA isoforms specifically expressed in tumors. The intended applications of discovered tumor specific isoforms include development of early tumor detection assays, identification of therapeutic targets for small molecules and monoclonal antibodies, and the design of vaccines. Development work has been done for ovarian serous adenocarcinoma (in conjunction with Cheryl Saenz, MD) and is now starting to encompass additional cancer types.

Drs. Barrett and Frazer, in collaboration with Drs. Carson, Schwab, Thistlethwaite, Jamieson, have recently reported on their use of transcriptome sequencing to study mRNA isoform expression differences in cell subpopulations of squamous cell lung cancer. Their investigation revealed a spectrum of new therapeutic options that could be effective for treating the disease and which would, importantly, likely target the subpopulation of cancer stem cells.

Dr. Harismendy leads a project to develop an ultra-deep targeted sequencing assay that can reliably detect and accurately measure the frequency of multiple somatic mutations present only in a fraction of the cells in a heterogeneous tumor. This assay was implemented to study 38-breast cancer specimens. In parallel, Dr. Harismendy has developed an analysis pipeline (Mutascope) dedicated to the identification of somatic mutations at low allelic fraction using amplicons sequencing. The presentation of Mutascope was published in the journal Bioinformatics and Mutascope is available for public download.

Dr. Harismendy is collaborating with Drs. Martinez and Schwab (Moores Cancer Center) to study the genetic and epigenetic changes associated with breastfeeding in Hispanic women with triple negative breast cancer. He is also leading a collaboration with Dr. Steve Howell (Moores Cancer Center) to identify the location of cisplatin-DNA adducts in vivo. The development of this method is important to understand the specific interactions between chromatin and the formation of adducts and why DNA damaging chemotherapy has strongly different sensitivity in different types of cancer. This project was awarded a pilot award from the San Diego Center for Systems Biology and, subsequently, an R21 award from the NCI, Innovative Molecular Analysis and Technology (IMAT) program.

Dr. Harismendy has collaborated with Dr. Karin (Moores Cancer Center) to study the mutational profile of two mouse models of hepatocellular carcinoma: spontaneous or genetic. The results showed extensive differences between the two models and are of primary importance to study the HCC progression in mouse. These results were included in a broader study published in the journal Cell (in press).

Drs. Harismendy and Frazer collaborated with Dr. Lowy (Moores Cancer Center) to study the mutations in a rare form of cancer: mucinous appendix cancer. This genome-wide study revealed two major signaling pathways, ras and PKA that are activated in this cancer. The study also highlights the molecular differences with colorectal cancer and offers new avenues for diagnosis and treatment.