| Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. The elucidation of the human genome sequence has made it possible to identify theses genetic alterations in cancers in unprecedented detail. To catalogue the genetic changes that occur during tumorigenesis in a systematic manner, we developed and utilized approaches for high-throughput genome sequencing. Using this technology, we determined the sequences of all the genes in the Reference Sequence database in breast and colorectal tumors. Based on analysis of exons representing 20,857 transcripts from 18,191 genes (thought to represent the vast majority of genes in the human genome), we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. The majority of these mutated genes were not previously known to be genetically altered in tumors and affect a diverse array of cellular functions. In order to prioritize genes for future studies, we developed various statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy. |
