Oct. 16, 2006 | A new paper from the venerable cancer team of Bert Vogelstein and the Johns Hopkins Kimmel Cancer Center is providing a timely mandate for a federally funded cancer genome project. The systematic search for gene mutations uncovered a surprisingly complex pattern in the number and variety of mutations that occur in two common forms of cancer. NIH director Elias Zerhouni hailed the study as "truly remarkable" and "groundbreaking."
Contrary to most textbooks, which typically portray cancer mutations as occurring in a neat linear sequence, the Hopkins team found scores of mutated genes in 22 breast and colon tumors. Ironically, that textbook picture owes much to seminal studies from Vogelstein's group in the 1990s on the multistep pathway to colon cancer.
In the latest study, published online by Science last month*, the Hopkins team conducted exhaustive screens of 13,000 highly annotated human genes, more than half the total in the human genome. The team of 29 investigators designed 135,000 PCR primers and screened 500 million bases of DNA sequence, at a cost Vogelstein estimates of $5 million. Most of the sequencing work and data generation for the study were done by Agencourt's Genomic Services (a subsidiary of Beckman Coulter).
The effort turned up an initial 800,000 sequence changes, which after various corrections for errors, silent substitutions, and so on, was whittled down to a group of potentially deleterious mutations in 189 genes - an average of 90 damaged genes in each tumor. Curiously, however, only two genes were mutated in both breast and colon cancer.
Many of the 189 mutant genes were not considered card-carrying cancer genes. "Scientists who have seen these data have told us that it keeps them up all night thinking," Vogelstein says. Additional studies suggest that of the mutant genes, about 11 in each tumor are directly tumorigenic. Extrapolating to the complete genome, this suggests mutations in about 17 genes cumulate in the evolution of a full-blown cancer.
The quantity and variation of mutations from one tumor to the next was unexpected but in hindsight fits with the notorious heterogeneity of cancer observed in the clinic. But by taking a "systems biology approach," Vogelstein's team has found that the many mutant genes congregate in a discrete set of 10-20 biochemical and signaling pathways. "The picture will become much clearer as the function of these genes and the ways they interact are better worked out," says Vogelstein, leading to new leads for diagnostics and drug development.
The Hopkins study was made possible by a range of bioinformatics tools to screen the human genome sequence. Ironically, it provides further justification to scale up the Cancer Genome Atlas (TCGA) (see "The Cancer Genome Atlas Pilot Launches," Feb. 2006 Bio-IT World, page 20).
As if on cue, the NIH has just launched the pilot phase of TCGA, selecting lung, brain, and ovarian cancers as the focus. The goal is to use large-scale genome analysis technologies to map all of the important genomic changes involved in cancer. TCGA will ultimately enable researchers throughout the world to analyze and employ the data to develop a new generation of targeted diagnostics and therapeutics for all cancers, paving the way for more personalized cancer medicine.
But not all researchers are enthusiastic about the financial drain and scientific benefit of TCGA. Their concerns - at a time when the NIH budget has flat-lined - are well taken, but such complaints sound awfully like the skepticism surrounding the dawn of the Human Genome Project almost two decades ago. We are still waiting for the medical bonanza from that endeavor, but few could argue with the short-term scientific payoff, which is spawning major advances in evolution, neuroscience, genetics and medicine.
With new sequencing technologies from the likes of Solexa, 454, and Agencourt Personal Genomics (now Applied Biosystems) gaining traction in the major genome centers where the bulk of TCGA will be conducted, the prospects for truly understanding the molecular basis of cancer are now within reach. For example, 454 announced this summer that, in collaboration with researchers at the Dana Farber Cancer Institute, it had developed a new method for detecting heterogeneous cancer mutations that could facilitate targeted therapies.
Regardless of which technologies win out, or which centers win the lucrative sequencing contracts, TCGA has a sublime medical and scientific importance, underscored by the latest findings from Hopkins. The project will be expensive, but with cancer still claiming one life every 60 seconds, we can't afford not to do it.
*T. Sjšblom et al. "The consensus coding sequences of human breast and colorectal cancers." Science Express Sept 7, 2006.
Email Kevin Davies.
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