With the emerging evidence of complex tumor heterogeneity, it is critical for us to profile and understand the complex evolution in tumor development. To do so, we desire to characterize the genome heterogeneity and complex evolution at microscopic resolution. Here we propose an exact linear amplification scheme for single cell whole-genome amplification, which will allow us to detect single nucleotide variations (SNVs) with the high accuracy comparable to the bulk sequencing. With this cutting-edge method development, we will be able to profile tumor heterogeneity at single cell resolution with unprecedented accuracy of SNV detection. Our immediate goal in this proposal is to apply this method to discover the onset of heterogeneity at low-grade of neoplasm and the sequential development of genome heterogeneity at the following higher grades of neoplasm. Overall, our goal is to develop a suite of highly promising single cell analytical technologies to gain an understanding of genomic variations in solid cancers. Success of the project will result in an integrated platform that will serve to overcome prevailing impediments in studying clinical samples. The research is expected to have a broad impact on basic research, clinical practice, and the development of therapeutic treatments for early intervention.
We will develop and validate an exact linear amplification method for single cell whole- genome amplification, which will allow us to detect single nucleotide variations (SNVs) with the high accuracy comparable to the bulk sequencing. We will access the potential of using single cell whole-genome sequencing for profiling and understanding the onset of genome heterogeneity and complex tumor evolution at microscopic resolution in tissue microenvironment.