Cancer Outcome Affected by Mutation Order Of Tumor Genes

Researchers have shown that cancer gene mutations in the right order can affect the outcome of the malignancy and the response to treatment. This is the first such study. 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 researchers from Germany, Spain and the U.K. conducted the study. The results were published in The New England Journal of Medicine, February 11, 2011.

From a scientific perspective, myeloproliferative Neoplasms (or Myeloproliferative Neoplasms) are one of the most fascinating cancers to research. They are blood disorders that are easy to test. Also, they are the first stages of cancer development, making it easier to identify the sequence in which their genes have mutated.

Anthony Green is the lead researcher of the research and also a clinical clinician at Addenbrooke's Hospital. He says that this experiment allows him to "look at single tumor cells". He and his collaborators took blood samples from 246 people and isolated cancerous and healthy cells. They then made colonies. Each colony contained identical copies of each cell (or clones), so the researchers had sufficient material to identify the gene profile of that cell.

Investigators compiled the genetic data from every blood sample to determine which mutations had occurred and the combinations. The investigators then looked for cells with a single mutation to determine which gene was responsible for determining the patient's first mutation. These cells should have been derived from cancerous cells that mutated first.

Two of the most important genes in the development of myeloproliferative neoplasms, previous studies have shown, are called TET2 and JAK2. TET2 acts as a tumor suppressor and can become defective. JAK2 enhances the effects of cell growth signals. When it becomes stuck in the "on", it acts as a accelerator for a running car.

According to the researchers, patients with the JAK2 gene mutation that occurred before TET2 were more likely than those who had TET2-first. Their cells also were less sensitive to antiJAK2 drugs. Another study found that the JAK2-first patient developed the disease earlier than their TET2-first counterparts (around 10 years after they were born). It doesn't always mean having TET2 mutate in the first place is better. This mutation has been shown to be predisposing people to develop full-blown leukemia.

Important caveat: Although the JAK2-first cells were sensitiver to anti-JAK2 drugs ruxolitnib than the others, this does not mean that those patients will be more likely to benefit from that treatment. Before this possibility is confirmed, another study will be needed that compares untreated and treated patients. "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 pointed out that computers were able to predict genetic mutation order in certain cases using only the information from other cancerous cells. The same calculation might be used in the diagnosis of other types.

It is currently more challenging to do similar studies in patients with lung cancer, breast tumors, or liver. The reason for this would be that the cells of these types are often more advanced and harder to access, so it will be easier to find them. However, single-cell sequencing is a new and highly advanced technique that could alleviate some of the difficulties. This type of sequencing involves researchers carefully removing the DNA from a cell and transcribing it into a complementary sequence ofRNA. Then, they copy the RNA sequence multiple times to be able to identify the genetic information in that sequence.

Myeloproliferative Neoplasms may be rare but the results highlight an important aspect of the rapidly growing field of precision medicine. Context is crucial when it comes to cancer treatment.