For the first time, researchers have proved that the order in which cancer genes mutate affects the type of malignancy that results and its response to treatment. Although the findings are specific to a particular group of preleukemic disorders known as myeloproliferative neoplasms, they suggest that scientists studying other types of tumors should start taking into account the timing of the underlying genetic mutations as a potentially critical factor in establishing an accurate diagnosis as well as in making choices about treatment. The study, which was conducted by investigators in the U.K., Spain and Germany, was published in the February 11 issue of The New England Journal of Medicine.

Myeloproliferative neoplasms are particularly compelling cancers to study, from a scientific point of view, for two reasons: as disorders of the blood, their cells are very easy to sample via routine blood tests; they represent the earliest stages of cancer growth, so it is easier to determine the order in which the genes in its cells mutated.

—Mapping the Cancer Genome [Feature]

The experiment "hinges on being able to look at single cells of a tumor," says Anthony Green, who led the study and is a researcher at the University of Cambridge and a clinician at Addenbrooke's Hospital. After taking blood samples from 246 patients, he and his colleagues isolated the individual healthy and cancerous cells, which they then grew into colonies. Because each colony consisted of identical copies (or clones) of the original cell, the researchers then had enough raw material to determine the genetic profile for that particular cell.

By collating the genetic information from all the cells in each blood sample, the investigators learned which genes had mutated and what combinations of mutations existed in the sample. They then determined which gene had mutated first for any particular patient by looking for cells that bore only a single mutation. By process of elimination, these cells must have descended from the very first normal cells to mutate toward a cancerous state.

—Personalized Medicine in the Genomic Era [In-Depth Report]

Two of the most important genes in the development of myeloproliferative neoplasms, previous studies have shown, are called TET2 and JAK2. TET2 is a tumor suppressor gene—so when it becomes defective, it's like disabling the brakes on a runaway car. JAK2 amplifies the effect of growth signals in a cell. So when it gets stuck in the "on" position, it's like pressing on the accelerator of a runaway car.

The researchers determined that patients in whom the JAK2 gene had undergone mutation before the TET2 gene were more likely to suffer blood clots, among other maladies, than their TET2-first counterparts, but their cells were more sensitive to anti-JAK2 drugs. A follow-up study showed that JAK2-first patients also tended to develop the disease at a younger age (in their late 50s and early 60s rather than about 10 years later). That doesn't necessarily mean that having TET2 mutate first was any better as that mutation is known to predispose people to developing full-fledged leukemia.

Another important caveat: Whereas the cells from the JAK2-first samples were more sensitive to the anti-JAK2 drug ruxolitnib, that does not necessarily predict those patients will benefit from treatment with that medication. Another study—which compares treated and untreated patients in a prospective manner—will need to be conducted before that tantalizing possibility can be confirmed. "We hope that this paper will lead to prospective studies [for treatment] and for the search in other cancers for whether or not the order of mutation matters in those cancers," says David Kent, one of the study's co-authors and an investigator at the Wellcome Trust–Medical Research Council Stem Cell Institute. Kent also noted that the group was able to develop computer algorithms that could predict the order of genetic mutation in some cases based solely on determining which other genes in the cancerous cells had also mutated. That kind of calculation may also prove applicable in other types of tumors, thereby simplifying the overall diagnostic process.

At present, conducting similar experiments in people with solid tumors of the lung, breast or liver, for example, would be much more difficult because the cancer cells are harder to get at and tend to be more evolved—which means they contain more mutations to sort out. But advances in a highly sophisticated technique called single-cell sequencing could mitigate that challenge. In essence, such sequencing requires researchers to carefully cut the DNA out of a cell, transcribe it into its complementary sequence of RNA, then copy that RNA sequence many times in order to have enough raw material to determine the genetic information contained in the original DNA sequence.

Although myeloproliferative neoplasms are rare, the findings underscore an important point in the nascent field of precision medicine. When it comes to treating cancer, context is everything.