Apply innovative technologies to explore cancer genome

Abstract

Molecular genetic alterations characterize the development of human cancer. Recent advances in molecular genetic technology and the success of the human genome project have empowered investigators with new tools in dissecting the cancer genome for discovery of new cancer-associated genes. The purpose of this review is to highlight the emerging molecular genetic methodologies and summarize their principles, applications, and potential technical challenges. The critical issue in sample preparation and a strategy that combines different molecular techniques to facilitate the identification of novel cancer-associated genes will be discussed. Digital karyotyping and array-based techniques including array comparative genomic hybridization and representational oligonucleotide microarray analysis have been recently developed to study the genomic landscape in human cancer. These innovations provide tools to quantitatively measure DNA copy number changes in cancer and to map those changes directly onto the human genome. Digital karyotyping is based on counting the sequence tags that are distributed in the human genome and thus, it provides a digital readout to precisely outline the amplified and deleted chromosomal regions. Array-based technologies, on the other hand, compare the content of cancer and reference genomes followed by localizing the amplified or deleted signals in chromosomal regions using an array hybridization technique. In addition, a high-throughput mutational analysis platform has been available for a large-scale mutational analysis by using an automated capillary sequencing device and sophisticated bioinformatic tools. A number of examples have demonstrated the promise of these new molecular genetic approaches in identifying several potential new oncogenes and tumor suppressors. As compared with conventional cytogenetics methods, digital karyotyping, array comparative genomic hybridization, and representational oligonucleotide microarray analysis provide an unprecedented mapping resolution that allows a precise localization of the amplified and deleted chromosomal regions. These technologies can be combined with gene expression profiling and high-throughput mutational analysis to facilitate the search for new cancer-associated genes. It is expected that applying these new technologies will lead to discovery of a host of novel oncogenes and tumor suppressors, which will have a significant impact in our understanding of tumorigenesis and in the clinical management of cancer patients.