Fueled by hundreds of millions of grant dollars, biomedical researchers have begun sequencing the genomes of thousands of tumor samples in the past few years, linking up scores of labs and sequencing centers in a massive effort to identify the genes behind major cancers. But a leading cancer geneticist this week questioned whether this strategy still makes sense. The skeptic is Bert Vogelstein, who spoke at a Monday plenary session on cancer genomes at the annual meeting of the American Association for Cancer Research in Washington, D.C. Vogelstein looked across all the studies published since 2007 that have sequenced the 21,000 or so protein-coding genes involved in cancer, known as the cancer “exome.” The analysis covered 78 tumor samples and eight cancer types (the majority of the studies were done by Vogelstein’s group). Vogelstein also threw in data for 22 medulloblastomas (a type of brain tumor) that his team has not yet published. Even at this early stage of the planned survey–with data on just 100 tumor samples—”we can already answer many of the fundamental questions about the cancer genome,” Vogelstein said. For example, tumors typically have from 30 to 80 single-base mutations, except for types that take less time to develop such as leukemia (about 10 mutations). Melanoma and lung cancer round out the high end (100 to 200 mutations) because they are caused by environmental carcinogens that cause lots of mutations. (Deletions and amplifications add a few more genetic glitches.) To Vogelstein this looked like the outline of a basic pattern that won’t change much. But he gathered some more details. 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But not all contribute to cancer. The challenge is to figure out which mutations are “drivers” and which are “passengers.” To pick out the drivers, Vogelstein assumed that mutations in suppressor genes had to truncate the gene’s protein; for oncogenes he included only mutations seen in at least two tumors. That distilled the gene count to just 319 potential driver genes, 286 of them tumor suppressors and 33 oncogenes. Nearly all these genes fall into 12 “core” signaling pathways, Vogelstein said. And that picture—about 320 genes in 12 pathways–is unlikely to change much even when thousands more tumor samples are sequenced, he argued. So far, the cancer exome projects have found only two new driver genes ( IDH1/2 in glioma and FOXL1 in granulosa tumors). Vogelstein predicts that most new driver mutations will be rare; and nearly all will be part of same 12 pathways. It may make more sense to target drugs on these pathways than on genes, Vogelstein said. That’s partly because 90% of the 320 driver mutations are tumor suppressors, which aren’t good drug targets. To treat such a mutation you must turn a gene that’s off back on, which is hard to do. Vogelstein summed up by saying that cancer has gone from “a complete black box” to something that “we really kind of understand.” The “sobering” part, he said, is that he doesn’t expect there will be many new genes or genetic breakthroughs. He has pinned his own hopes for preventing cancer deaths on using genetics to diagnose cancers early, when they’re more treatable. Vogelstein isn’t the only one questioning the wisdom of pricey cancer genome projects. (The U.S. National Cancer Institute’s Cancer Genome Atlas (TCGA), the main one, has cost $375 million so far; it is part of an international cancer genome consortium that aims to sequence 25,000 tumor samples for a total of $1 billion.) The Massachusetts Institute of Technology’s Robert Weinberg told ScienceInsider that he considers TCGA “money poured down a hole. Sequencing endless more cancer genomes isn’t going to tell us more than we already know.” But cancer geneticist Todd Golub of the Broad Institute in Cambridge, Massachusetts, who recently debated the cancer genome projects with Weinberg in Nature, disagrees. There’s more to be learned by finding rare mutations, he says. “There will be some pathways we don’t know about that are totally new,” Golub says, and “we won’t get that out of a few genomes.” UPDATE 4/26/2010:NCI’s Anna Barker and Mark Guyer of the National Human Genome Research Institute, who oversee The Cancer Genome Atlas, told ScienceInsider that they’re not persuaded by Vogelstein’s argument that 100 tumor genomes are enough to predict what will be learned from many more cancer genomes. “That’s a nice opinion, and where’s the data to demonstrate it?” says Guyer. Adds Barker: “I am stunned that he [Vogelstein] made some of these comments.” She says that having “a robust set of samples and a robust set of data” is already providing insights that can’t be gleaned from smaller studies, such as delineating clinical subtypes of gliomas based on epigenetics. “The thing that really differentiates this project from anything done in the history of medicine to date is that it’s really moving us towards quantitative cancer biology,” Barker says.