A new set of findings from The Cancer Genome Atlas (TCGA) project was published recently, in the October 16, 2013 issue of the journal Nature.
Previous reports from this large ongoing project have shown that tumor cells for individual cancer types, such a breast cancer, colon cancer, etc. sometimes contain many more types of genetic mutations than was previously known.
By contrast, this new report looks at cancer genome sequencing in a different way–comparing mutations across types of cancer.
Overall, TCGA has been generating interesting, though somewhat controversial, findings.
In this recently reported study, the scientists analyzed about 3,800 tumor samples from 12 different types of cancer and found a total of 127 different types of genetic mutations that occur across at least some of the tumor types. The well-known BRCA1 and BRCA2 mutations, which are usually inherited and increase risk for breast cancer, are among them. But most of the 127 types of mutations are so-called “somatic” mutations that occur during an individual person’s lifetime. The causes of these types of mutations are mostly unknown–a few are caused by known factors in the environment, while it is believed that many simply occur at random.
Perhaps the most interesting finding in this particular study was that, for any individual tumor, there are only two to six mutations that actually drive the cancer. Driver mutations may, for example, activate cellular processes that promote uncontrolled cell division or turn off processes that kill mutated cells before than can multiply and become malignant tumors.
There are differences of view as to just what benefit ultimately will come from the ongoing effort to sequence the cancer genome. In “What’s the Point of Finding Cancer Mutations?” in Slate, Jessica Wapner argues that what cancer genomics tells us about the disease can be fascinating, but there’s little we can do with the information. She writes:
For nearly all the genetic mutations and resulting cellular mix-ups that have been chronicled, no drug exists to target that root cause. And not for lack of trying. Pharmaceutical companies have been attempting for years to make a drug to target the protein product of mutant KRAS, but no luck. Some targets are considered “undruggable”–maybe the shape of the errant protein is too flat or undulating for a drug to cling to. Sometimes the target is hit with a drug, but the rapidly mutating cancer finds a workaround before the tumor can be annihilated.
The other view is more optimistic that we will eventually be able to develop drugs to target driver mutations and that we’ll likely be able to derive a great deal of benefit from strategically combining drugs that together home in on a few key drivers. In a balanced article that explores both perspectives entitled “Future Frontier: Fighting Cancer at the Genetic Level” in CureToday, Laura Beil describes the more optimistic view this way:
The idea is that by taking a sample of a tumor and rapidly figuring out which instructions are wrong, doctors will know where the cancer drug needs to work. (If the cancer is occurring because certain genetic mutations are allowing specific proteins to take over a cell, you know specifically what task a drug needs to accomplish.) A version of this kind of tailored care is available now only for a handful of well-studied mutations, such as HER2 in breast cancer and EGFR in colon and lung cancers. Doctors envision a day when they can expose all a tumor’s genetic tricks. “I think this is going to be standard of care, and not in 10 years, but in a few years,” says Michael Snyder, director of the Stanford Center for Genomics and Personalized Medicine in Stanford, Calif. In the not too distant future, he continues, “I can’t imagine getting cancer and not getting your genome sequenced.”
But it seems there is quite a ways to go before genomic sequencing can benefit most patients. In order for knowledge about the precise mutations in patients’ tumors to directly benefit those patients, more research is going to be needed to identify existing drugs (or, if necessary, develop new drugs) that can effectively target specific mutations or combinations of mutations. And to accomplish that, more innovative approaches to testing drugs are going to be needed.
Some movement in that direction is already occurring. A November 7, 2013 article in Forbes describes a new clinical trial in lung cancer in which patients’ tumors will be scanned for 16 different genetic abnormalities. A number of different drug companies will participate in the trial, providing up to two dozen different drugs. Patients will be assigned to receive drugs based on the specific mutations their tumors contain. The article notes that “other studies have tried to examine multiple drugs at once, but this will be the first one aimed at getting the effective Food and Drug Administration approval.”
It’s too early to tell to what extent, and how soon, patients may benefit from the ongoing cancer genome studies, but some experts do believe the timeline won’t be extremely long, and encouragingly, there are some efforts underway to try to translate research findings into clinical application. This will be a line of research to follow closely as it continues to develop.
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