Cancers, including brain cancers, arise due to deleterious changes to DNA — the genetic material that provides life instructions to our cells. The most common and easily recognized DNA alterations are mutations that alter a protein-coding sequence within the one of the 20,000 plus genes in our DNA. These mutations, along with other genetic and epigenetic changes, then in turn alter the amount and sequence of the RNA and protein expressed in a cancerous cell.
Many of our projects use the latest techniques to measure gene expression in malignant cells and experimental systems we engineer to study cancer related genes. Studying the transcripts expressed in cancer cells was the first functional genomics tool we have applied to studying cancer cells. As part of this work, our lab organized the Cancer Genome Anatomy Project’s SAGE database known as SAGE Genie. SAGE Genie is one of the largest and most commonly used Cancer Gene Expression Databases.
This image shows an example from the ‘SAGE Genie Anatomic viewer’ of a gene that has high expression only in glial tumors.
Some of our projects are now trying to determine why certain genes are over-expressed in brain cancers, compared to normal brain, and evaluating if these genes are good therapeutic targets.
High-throughput Mutation Screens
Of particular interest to our lab is the identification of cancer-causing gene mutations.
We have already identified new mutations in kinase genes (FGFR1 and PDGFRA) that are probably genetic changes that lead to tumor formation in glioblastomas. This work is published in PNAS.
Using Digital Karyotyping — a technique to map amplifications and deletions in high resolution along the entire genome — we found that the OTX2 gene is amplified in some medulloblastomas. Using SAGE we also found it was overexpressed in about 60% of medulloblastomas. We are currently working on the functional and therapeutic implications of this medulloblastoma oncogene. We are currently scaling up to perform larger screens for brain tumor mutations.
Starting in 2006, we now have NIH funding to support a genomics project for high-throughput screens of glioblastoma genomes.
This Glioblastoma Genome Project is in conjunction with the Venter Institute.