Genomic mutation studies unlock details on cancers

Researchers unveiled a comprehensive look at the genetic mutations responsible for two cancers Wednesday as part of a broad government-sponsored initiative to enlist the power of genomic information to transform cancer treatment.

In separate studies, scientists identified essentially all of the major molecular aberrations that drive development and growth of endometrial cancer, which forms in the lining of the uterus, and a blood cancer known as acute myeloid leukemia. In both cases, researchers said, the reports provide important new insights that could change how patients are treated and affect development of new cancer-fighting drugs.

The studies are part of the Cancer Genome Atlas project, an initiative funded by the National Institutes of Health to map genetic information from 10,000 tumors covering some two dozen cancers. The project has already yielded findings in other cancers, including breast, lung and colon that are helping to alter fundamentally medicine's views about the western world's leading killer.

"Cancer is a disease of the genome," said Brad Ozenberger, program director for the Atlas studies at the National Human Genome Research Institute, which along with the National Cancer Institute is spearheading the project. With recent advances in sequencing technology, scientists "are able to really dive in deep and find out what is causing the disease."

Cancer has long been identified and treated based on the organ in which it arises—breast, prostate, or skin, for instance. But emerging genomic information shows that "a lot of these different cancers share a similar genetic identity," said Richard K. Wilson, director of the Genome Institute at Washington University in St. Louis. "We started…thinking that we should treat cancer based not on what tissue it comes from but on what genes are mutated."

That insight is prompting drug makers to develop drugs that target specific mutations in patients' tumors. A new term is emerging to describe this approach: precision medicine.

There are big hurdles. A drug that is effective against a mutation in, say, skin cancer may not have any impact against the same mutation in colon cancer. Experience so far suggests a precision approach may ultimately require multiple agents to attack all the genetic drivers of a tumor, which typically manage eventually to find ways around a single effective drug.

Such therapies also are proving to be expensive. But cancer researchers are convinced that genomic-based strategies offer a chance to make major progress against the disease. Dr. Wilson called it a paradigm shift: "The more cancer genomes we look at the more that is reinforced."

Some 50,000 new cases of endometrial cancer are diagnosed in the U.S. each year, with about 8,000 deaths. Current methods have identified two tumor types. Type I tumors are typically treated with radiation after the cancer is surgically removed, and the prognosis for recovery is good. Type II tumors require surgery plus chemotherapy, and often have poorer outcomes.

But a genomic analysis of 373 endometrial tumors by Atlas researchers identified four subtypes instead of two, each possibly requiring different treatments. In addition, the scientists found that about 25 percent of tumors that pathologists classified as high-grade type I had molecular traits similar to type II, suggesting the need for more aggressive treatment.

The findings need to be validated in clinical trials, said Douglas A. Levine, a gynecologic oncologist who leads the Gynecology Research Laboratory at Memorial Sloan-Kettering Cancer Center. But "we're now going to put more patients into the group that should get more aggressive treatment after surgery," he said. The endometrial cancer findings were published by the journal Nature.

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