Anomalies of the genome, such as congenital chromosomal imbalances, can be present from birth or can arise during cell division and lead to formation of cancer. Progression of cancer can be followed by monitoring changes in the genome. For instance, allelic deletions of tumor suppressor genes and amplifications of oncogenes are well known events in carcinogenesis. The primary goal of this project is to develop a high resolution array-based approach to detecting and monitoring changes in tumor samples. A secondary goal is to detect microdeletions and amplifications in congenital chromosomal disorders. The proposed work will focus on developing DNA copy and loss of heterozygosity (LOH) measurements using our novel whole genome genotyping (WGG) platform. The WGG technology was developed, in part, through phase I funding. Under phase I, we developed a whole genome amplification protocol and an arraybased primer extension assay that enabled direct readout of the genome - both copy number and genotypes. This development obviates the need for the original proposed complexity reduction step (reduced representation). The number of genotypes that can be read out from a single sample is limited only by the number of probes on the array. The proposed work will use a WGG array that is currently under development to perform genotyping and copy number analysis at the same time, at an average resolution of approximately 30 kb across the genome. This revolutionary assay system will allow regions of genomic alteration to be precisely defined accurately and robustly, and has the potential to be used directly in clinical applications. Once fully developed, the assay will be employed to characterize biological tumor/normal sample pairs as well as congenital chromosomal imbalances.
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