When the co-authors Richard Wilson, Ph.D.D., director and co-director of the Genome Institute, respectively, and their colleagues have sequenced the genome of cancer cells in mice, they found genetic mutations in the three genes, each of which a single letter change in DNA sequence and disrupt the instructions for making proteins.Unlike sequencing studies that focus only on genes, which represent only 1 % of the whole genome, genome sequencing to capture the full range of genetic alterations in DNA, including large insertions, deletions and other structural changes .
APL is a cancer success story: once the most deadly form of leukemia, APL is now highly curable. However, about 20 % of patients have relapsed after standard treatment, emphasizing the need for a more effective treatment.
There was a debate going on for 15 years on the fact that mouse models of cancer are linked to cancer that develops in people, he says. The sequencing of the genome of this, I think the answer is clear: this mouse model is very similar to human disease This gives us a new way of using the entire genome to quickly identify the most relevant mutations in human cancers .
The research is funded by the National Institutes of Health, Barnes-Jewish Hospital Foundation, the National Cancer Institute and the National Center for Research Resources.
Other authors of the study of Ana-Maria Iosif, Fam Baguio, Ian C.S. Intentional communication and social behavior in children development virtually unchanged, while the children diagnosed with autism as a result of decreased drastically.
But the effort is time consuming. Cancer cells typically acquire several hundred mutations, the vast majority are basic changes that occur naturally throughout the life of a person. The challenge is to sift through the genetic noise to find the handful of mutations in each tumor that drive cancer development.
Ley said the new research also highlights the value of mouse models of cancer to find significant changes in patients.
Ley and his colleagues hypothesized that their work could be simplified if they have sought mutations in mouse models of cancer. These mice are inbred, suggesting that mutations in less background.
The scientists who pioneered the sequencing of the genomes of patients to find new genetic mutations responsible for the disease have turned their attention to a laboratory mouse is a workaholic.
We also evaluated a JAK inhibitor in 10 mouse APL tumors and each of them answered, even those without a mutation in the gene, Wartman said. This suggests that JAK1 is part of a process essential for the disease of cancer. Interestingly, JAK inhibitors are already in clinical trials for a number of cancers.
For this study, the researchers inserted into the mouse genome a mutated human called PML-RARA, which is known to initiate APL patients. Then they waited a year for full-blown leukemia to develop.
This approach gives us the ability to quickly assess whether mutations in human tumors are likely to be important, said lead author Timothy Ley, MD, T. Apple Professor of Oncology. If we find mutations that occur in mouse models and see these same mutations, however rare, in human tumors, are very likely to be appropriate.
One of these mutations in JAK1, also occurred in six of the 89 other APL mouse tumors studied. In addition, the mutation was identical to that of other research groups have recently identified in a patient with APL and in other patients .
We expect to accelerate our ability to determine whether mutations in patients that are important for the progression of the disease, says Wilson. If we find the same mutations in human tumors and in a mouse model of disease, when we know they are likely to be relevant, although we saw only a small fraction of mutations in patients.
During this waiting period, the bone marrow cells in mice are thought to acquire additional mutations that transform cells in leukemia correct. The purpose of this study was to find these mutations cooperate and determine whether they also occur in patients with leukemia.
This work is really important to me but also for many other cancer patients and cancer survivors who want to know why the cancer in the first place, Wartman said. We believe that such studies may help answer that question.
For the future, the researchers say that will complement their efforts to sequence human cancer genomes with their counterparts in the mouse genome, when mice are good models.
By establishing that the mutation occurs in other mouse tumor samples and in patients with leukemia, who tells us this mutation is a driver, is almost certainly relevant to the progression of cancer, said Ley.
The researchers also discovered a large deletion in Kdm6a genes in the genome of mouse tumors. A similar deletion was found in the genomes of three of the 14 mice studied, and APL, in a sample of human AML.
Deletions in the same gene have been associated with human cancers, including cancers of the kidney, esophagus and other blood cancers.