Analysis of Genomic Alterations in Cancer

Cancer is driven by a selection for mutations that include single nucleotide substitutions, short indels, and large-scale rearrangements of the genome [e.g., chromosomal inversions, translocations, segmental deletions, segmental duplications, and changes in chromosome copy number (aneuploidy and polyploidy)]. The frequency of these events varies greatly among tumors. For example, some tumors exhibit a large number of single nucleotide mutations but relatively normal chromosomal organization, while other tumors exhibit extensive chromosomal aberrations and rearrangement. In some types of cancer, these large-scale rearrangements produce changes in gene structure and regulation that are directly implicated in cancer progression and are targets for cancer therapeutics. A classic example is the Philadelphia chromosome [1], a 9;22 translocation observed in chronic myeloid leukemia. This translocation results in the ABL-BCR fusion protein [2] that is targeted by the drug Gleevec [3]. Another example is the chromosome in Burkitt’s 8;14 translocation lymphoma. This translocation activates the c-myc gene by placing it under the control of a strong promoter of an immunoglobulin gene [4]. In contrast to these and other well-characterized translocations in leukemias and lymphomas, solid tumors frequently exhibit many chromosomal aberrations [5]. However, very few aberrations have been found to be recurrent across multiple patients, and thus it was believed that fusion genes like ABL-BCR were nonexistent in solid tumors.