There are three major projects going on in my laboratory. The first project is the study of the common fragile sites, which are regions of profound genomic instability found in all individuals. The common fragile sites are large regions (1-10 Mbs) and contained within many of them are extremely large genes, some which are 1-2 Mbs in size. These genes appear to play important roles in cancer development (several have already been demonstrated to function as tumor suppressors) and they are also involved in normal neurological development. Two genes that we are particularly interested in are RORA (an orphan retinoic acid receptor) and Dab1 (the human homolog of the disabled locus from Drosophila). When these genes are inactivated they result in mice with neurological defects (Quaker for RORA, and staggerer for Dab1), hence weâ??re investigating how these genes may be linking neurological development and cancer. Many of the large common fragile site genes also appear to be involved in the cellular response to stress (particularly oxidative stress), hence weâ??re also analyzing this, especially with RORA and Dab1.

The second project that we are working on is the investigation of non-coding transcripts. The coding portion of the genome (that portion that codes for protein) is only 2% of the genome. The transcriptional output of the genome is considerably greater than just the coding transcripts, hence the majority of the genome codes for non-coding transcripts. We have utilized the newest microarrays, called tiling arrays (which contain tiled oligonucleotide probes across the entire non-redundant portion of the genome) to investigate the genomes transcriptional output especially in response to environmental stresses (we utilized hypoxic stress and the cigarette carcinogen NNK). We have found hundreds of thousands of non-coding transcripts and many of these are stress-responsive. One group of non-coding transcripts that we are particularly interested in studying are a group of transcripts that are abundantly expressed and also highly evolutionarily conserved. We have now found that many of these transcripts are aberrantly expressed in cancer and a number of them are also mutated in different cancers. We are utilizing microarray and siRNA technologies to understand the function of these highly conserved non-coding transcripts in both normal and cancer cells.

The third project that weâ??re working on is the molecular genetics of head and neck cancer. This cancer has two different etiologies; one involving drinking and smoking and another found in a younger patient population without such bad habits. This may be caused by viral infection such as human papilloma virus. In cancers of the tongue there is also a group of non-smokers or drinkers who are developing this disease early, but it is unknown what is the causative agent (or virus). We are therefore using microarray analysis of gene expression, as well as array comparative genomic hybridization to compare head and neck cancers from a population of drinkers and smokers to those without drinking and smoking. The goal is to delineate important pathways involved in the development of these two different types of head and neck cancers.