Researchers Find More Genetic Drivers on Cancer's Highway

CAMBRIDGE, United Kingdom—The number of mutated genes driving the development of cancer is larger than previously believed, a finding that unveils a new challenge for researchers. Moreover, each cell type carries many "passenger" mutations that have hitchhiked along with driver mutations, the mutations that cause cancer. Cancer biologists now need to distinguish the drivers from the larger number of passengers. "The human genome is a vast place and this, our first deep systematic exploration in cancer, has thrown up many surprises," said Michael R. Stratton, MB, PhD, co-leader of the Cancer Genome Project at the Wellcome Trust Sanger Institute, Cambridge, UK, which funded the research. "We have found a much larger number of mutated driver genes produced by a wider range of forces than we expected."

The new results emerged from the sequencing of 274 megabases of DNA code that corresponded to more than 518 protein kinase genes in 210 cancers. The research yielded more than 1,000 somatic mutations, including possible driver mutations in 120 genes, most of which were not seen before.

The systematic sequencing of the DNA enabled the researchers to trace the evolutionary diversity of the cancers and discover the new cancer-related genes. "For example, we found that a group of kinases involved in the fibroblast growth factor receptor [FGFR] signaling pathway was hit much more than we expected, particularly in colorectal cancers," said P. Andrew Futreal, MB, PhD, co-leader of the Cancer Genome Project.

The study, published in the March 8 issue of Nature (Greenman C et al: 446:153-158, 2007), focused on the kinases, which can act as relay switches to turn gene expression on and off in cells to control cell behaviors such as cell division. The study found statistical evidence for a large set of mutated protein kinase genes implicated in the development of about one-third of the cancers studied, including cancers of the breast, lung, colon, stomach, ovary, kidney, and testis. "Given that we have studied only 518 genes and limited numbers of each cancer type, it seems likely that the repertoire of mutated human cancer genes is larger than previously envisaged," the researchers said.

The team also found important coded messages within the mutations they studied. The type of mutation varied between individual cancers, reflecting the processes that generated the mutations. Some of these processes were active many years before the cancer appeared. Some of these mutation patterns can be deciphered, such as damage from ultraviolet radiation or the cancer-causing chemicals in tobacco. Others require future decoding.

"The time is right to apply the powerful tools of genomics to obtain a comprehensive view of what goes wrong at the DNA level in cancer," said Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute at the National Institutes of Health. "The important and interesting data on protein kinases in this report . . . further encourage the conclusion that a full assault on the cancer genome will yield many opportunities to revolutionize diagnosis and treatment."

On the Web

For more information on the Cancer Genome Project, please visit: www.sanger.ac.uk/genetics/CGP/. For the COSMIC (Catalogue of Somatic Mutations in Cancer) database of cancer mutations, visit: www.sanger.ac.uk/genetics/CGP/cosmic/.