Ovarian cancer is difficult to detect early, and fewer than half of the 22,000 women diagnosed annually in the United States will live more than 5 years. Today, researchers released the results of a massive hunt to track down the genetic changes that drive tumor growth in this dreaded disease. Although the study found no new cancer genes, it revealed surprisingly disordered DNA. Researchers say certain drugs might help patients by counteracting the dysfunctional genes.
The study is one of dozens around the world that are exploring the genetic underpinnings of cancers by systematically sequencing tumors. This project, part of the U.S. National Institutes of Health's The Cancer Genome Atlas (TCGA), focused on high-grade serous ovarian adenocarcinoma, an aggressive disease that accounts for about 70% of the 14,000 deaths from ovarian cancer in the United States each year. Fifteen teams analyzed nearly 500 patients' tumors for genetic aberrations and sequenced the protein-coding DNA of 316 samples—by far the largest cancer sequencing effort to date.
Nearly all of the samples (96%) had mutations in TP53, a gene that helps suppress cancer and is often damaged in tumors. Some had mutations in other cancer genes, including the breast and ovarian cancer risk genes BRCA1 and BRCA2. Apart from TP53 and the BRCA genes, most of these broken genes appeared only in a few tumors, meaning that any drug therapy would have to be tailored to the individual patient. "For some tumors, it's a much harder problem than we thought," says project leader Paul Spellman of Lawrence Berkeley National Laboratory in California.
The project yielded other useful information, however. By analyzing patterns of gene expression, researchers sorted ovarian tumors into two types that correlated with how long patients survived. These two groups of long-term and short-term survivors hint at differences in the biology of the disease, Spellman says.
The study also found "enormous structural variation," including missing or extra copies of cancer genes, says Spellman, leading to over- or underexpression of proteins that might drive cancer growth. That sets this cancer apart from most others. More than 20 of the overexpressed genes can be targeted with existing drugs to muffle them, suggesting patients could be tested and matched to these drugs, says TCGA investigator Douglas Levine of Memorial Sloan-Kettering Cancer Center in New York City.
Looking across all the genetic glitches, investigators found that half the tumor samples had flaws in a cell process for repairing DNA known as homologous recombination. These tumors might yield to a new kind of drug known as a PARP inhibitor that kills cancer cells by hijacking the cell's ability to mend DNA breaks.
The PARP inhibitors have proved disappointing in late stage trials for breast cancer. But so far in trials for ovarian cancer they have blocked tumor growth in many patients, Levine notes. "If these [TCGA] investigators are right, those trials will be successful," cancer geneticist Bert Vogelstein of Johns Hopkins University in Baltimore, Maryland, says.
The study, published online today in Nature, is the second cancer completed by the TCGA, a $375 million-and-counting project launched in 2006 that is sequencing more than 20 cancer types.
Some researchers suggested that TCGA's ovarian cancer project has been disappointing because it didn't find any novel cancer genes and most genes it did find are rare. "It is a useful scaffold ... for future discoveries but hasn't [of itself] found anything new," says James Brenton of Cancer Research UK in Cambridge, whose group reported last year that nearly all high-grade serous ovarian cancers have TP53 mutations. And like other TCGA efforts, the project cost "a lot of money," he notes. TCGA is still worth it, he says, but "the return on the investment [for this cancer] is less than for other tumor sites."
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