A Detailed Genetic Portrait of the Deadliest Human Cancers

Abstract

CANCER GENETICS Three studies published this week have given researchers their most detailed look so far at the genetic mutations that underlie the deadliest of human cancers: pancreatic cancer and the brain tumor glioblastoma. They have firmed up the role of key genes and also found that scores of aberrant genes are involved in relatively few cell signaling pathways. One study also unearthed a gene never before linked to cancer that is mutated in a substantial fraction of glioblastoma tumors. “It shows we can still be surprised” by the biology of cancer, says Michael Stratton, who oversees a cancer gene sequencing project at the Sanger Institute in Hinxton, U.K. These studies are all based on the premise that information gleaned from systematically cataloging the main mutations in tumors will be worth the high cost. Three years ago, when genome sequencer Eric Lander of the Broad Institute in Cambridge, Massachusetts, proposed spending $1.5 billion on what is now called The Cancer Genome Atlas (TCGA), skeptics helped persuade the U.S. National Institutes of Health to start with a 3-year, $100 million pilot project. One of the glioblastoma studies is the first fruit of that effort. Meanwhile, a team led by Bert Vogelstein, Kenneth Kinzler, and Victor Velculescu at Johns Hopkins University in Baltimore, Maryland, had begun a private cancer genome project, starting with breast and colorectal cancer ( Science , 8 September 2006, p. [1370][1]). Now this team and collaborators have sequenced the coding regions of 20,700 genes—nearly all the known genes in the human genome—in 22 glioblastoma and 24 pancreatic cancer samples. They also looked for abnormalities in gene copy number and gene expression. In two papers published online by Science this week ([www.sciencemag.org/cgi/content/abstract/1164382][2] and -[1164368][3]), they report finding hundreds of genes that were mutated in these two cancers. There were an average of 63 altered genes in each pancreatic tumor and 60 per glioblastoma. The mutations varied from tumor to tumor, but the most important tended to fall in the same cell pathways. For example, 12 specific pathways were disrupted in at least 70% of pancreatic tumors. “It points to a new way of looking at cancer,” says Vogelstein, who suggests that treatments should target these pathways, not the products of single genes. One of the altered genes found in the glioblastoma study, IDH1 , appeared in 12% of tumors, and more often in younger patients and those with secondary tumors, the Johns Hopkins team reported. A change in an amino acid of the encoded protein seems to help patients with this mutation live longer than others with glioblastoma. The third study, published online by Nature , analyzed more than 200 glioblastoma samples. It surveyed all the samples for genetic alterations such as changes in copy number and probed about half the samples for mutations in 600 genes already implicated in cancer, says co-leader Lynda Chin of the Dana-Farber Cancer Institute in Boston ( Science , 4 July, p. [26][4]). The study found many of the same aberrant genes that the Johns Hopkins team uncovered—but not IDH1 , which was not among the genes the team sequenced. Their larger sample set will serve as a reliable reference on how frequently mutations occur in glioblastoma, including several genes for which the evidence was limited until now, says Chin. Having methylation data and samples from patients who received treatment also allowed the team to finger mutations in DNA repair genes that may help explain why tumors that initially respond to temozolomide, the main drug for glioblastoma, can become resistant to subsequent therapies. ![Figure][5] Probing a killer. Two new studies tally genetic glitches that cause the brain tumor known as glioblastoma, orange in this image of brain cells. CREDIT: R. BICK, B. POINDEXTER, UT MEDICAL SCHOOL/PHOTO RESEARCHERS, INC. TCGA is preparing follow-on papers, for example on using the molecular data to classify subsets of tumors, Chin notes. It will also expand the search: The project, which is also studying lung and ovarian cancers, will use new technologies to sequence thousands of genes in each tumor. “I see them [the public and private glioblastoma studies] as wonderfully complementary,” says pathologist Paul Mischel of the University of California, Los Angeles, who studies glioblastoma. Other researchers who hope to use the findings to improve cancer treatment agree. “This is a start and a wonderful start,” says Santosh Kesari, a neurooncologist at Dana-Farber. [1]: /lookup/doi/10.1126/science.313.5792.1370 [2]: http://www.sciencemag.org/cgi/content/abstract/1164382 [3]: http://www.sciencemag.org/cgi/content/abstract/1164368 [4]: /lookup/doi/10.1126/science.321.5885.26a [5]: pending:yes