A massive U.S. initiative to genetically characterize 10,000 tumors has officially come to a close. Started as a$100 million pilot project in 2006, The Cancer Genome Atlas (TCGA) is now the largest component of the International Cancer Genome Consortium, a group of scientists from 16 countries that has identified nearly 10 million cancer-related mutations. The question now is what to do next. Some researchers want to continue to focus on sequencing; others want to expand their work so they can explore how the mutations already identified have an impact on cancer formation and progression. Bruce Stillman, director of the Cold Spring Harbor, N.Y., laboratory, said, “The completion of TCGA declares a triumph.” He said, “For a given cancer, there are always new mutations associated with it that are discovered. The question is: What is the cost-benefit ratio?” Stillman was an early advocate of the project, although some researchers were concerned that it would lead to a loss of funds to fund individual research. The project, initially planned for three years, was eventually expanded to a more than five-year program. In 2009, TCGA received an additional$100 million from the National Institutes of Health (NIH) and$175 million from incentive funds attempting to stimulate the U.S. economy in the midst of a global recession. This project did not initially go well. Sequencing technology at the time could only target fresh tissue that had been rapidly frozen. However, most clinical biopsies were fixed in paraffin and stained by pathologists. Louis Staudt, director of the Cancer Genome Office at the National Cancer Institute (NCI) in Bethesda, Maryland, noted that the cost of finding and paying for fresh tissue samples became the biggest expense of the project. Another issue is the complexity of the data. While some mutations may contribute to cancer progression, along with less commonality among tumors, most mutations form a dizzying hodgepodge of genetic abnormalities. Drug testing for specific mutations often quickly leads to another problem: cancers often rapidly develop resistance, which is generally achieved by using activation of different genes and thus bypassing the cellular processes blocked by the treatment. Johns Hopkins University, Baltimore, Md. Despite these difficulties, nearly every aspect of cancer research has benefited from TCGA, notes Bert Vogelstein, a cancer geneticist at Johns Hopkins University in Baltimore, Maryland. Researchers have used the data to come up with new ways to classify tumors and discover previously unrecognized drug targets and carcinogens. But some researchers believe sequencing results can still provide more information. Last January, a statistical analysis of mutation data from 21 cancers showed that researchers could still potentially identify clinically useful mutations from sequencing results. Last Dec. 2, Staudt announced that once the TCGA is completed, the NCI will focus on sequencing three cancers – ovarian, colorectal and lung cancer. The agency will then evaluate the results of this additional work to determine whether additional cancers should be added to the sequencing armada. But this time, the study will be able to integrate detailed clinical information about a patient’s health status, treatment history and response to treatment. That’s because researchers now have access to paraffin-embedded samples, and they can mine data from past clinical trials while studying how genetic mutations affect a patient’s prognosis and response to treatment. Staudt said the NCI will launch an initiative calling for sequencing samples to be collected in clinical trials using the methods and analysis pathways established by the TCGA. Tom Hudson, director of the Toronto Cancer Institute in Canada, said the remainder of the International Cancer Genome Consortium’s work will likely follow a similar strategy and will release plans for a second round of projects this February.