Acute Myelogenous Leukemia (AML) has a 5 year survival rate of approximately 20% and kills about 8,000 people/year in the U.S. Until recently, only two mutations had been identified as contributing factors, but researchers at the Washington University School of Medicine in St. Louis have used high-throughput-sequencing to produce the first complete genome of a cancer. The study will be published in today’s edition of the journal Nature.
The patient, a woman in her 50’s with AML, succumbed to her illness two years ago, but her legacy lives on as her cell lines continue to provide new insights into the DNA changes involved in AML. High throughput sequencing uses sophisticated computer analysis techniques to compare the complete genome from the patient’s healthy skin cells to patient’s AML tumor cells, the ones that eventually replaced her bone marrow. Researchers were able to “quickly” identify 8 new mutations that appear to contribute to a variety of sub-cellular processes leading to cancer proliferation. Some of these pathways were completely unexpected.
From a Washington University School of Medicine in St. Louis press release:
Like most cancers, AML – a cancer of blood-forming cells in the bone marrow – arises from mutations that accumulate in people’s DNA over the course of their lives. However, little is known about the precise nature of those changes and how they disrupt biological pathways to cause the uncontrolled cell growth that is the hallmark of cancer.
Previous efforts to decode individual human genomes have looked at common points of DNA variation that may be relevant for disease risk. What’s striking about the new research is that the scientists were able to sift through the 3 billion pairs of chemical bases that make up the human genome to pull out the mutations that contributed to the patient’s cancer.
"Until now, no one has sequenced a patient’s genome to find all the mutations that are unique to that person’s disease," says lead author Timothy Ley, M.D., a hematologist and the Alan A. and Edith L. Wolff Professor of Medicine. "We didn’t know what we would find, but we felt that the answers to why this patient had AML had to be embedded in her DNA."
To date, scientists involved in large-scale genetic studies of cancer have not gone so far as to do a full side-by-side comparison of the genomes of normal cells and tumor cells from the same patient. Rather, most earlier studies have involved the sequencing of genes with known or suspected relationships to cancer, a method that likely misses key mutations.
"The determination of the first complete DNA sequence of a human cancer genome, and its comparison to normal tissues of the same individual, is a true landmark in cancer research," says geneticist Francis Collins, M.D., Ph.D., former director of the National Human Genome Research Institute. "In the past, cancer researchers have been ‘looking under the lamppost’ to find the causes of malignancy – but now the team from Washington University has lit up the whole street. This achievement ushers in a new era of comprehensive understanding of the fundamental nature of cancer, and offers great promise for the development of powerful new approaches to diagnosis, prevention and treatment."
Based on their current understanding of cancer, the researchers suspect that the mutations occurred sequentially. The first mutation gave the cell a slight tendency toward cancer, and then one by one, the other genetic alterations were acquired, with each contributing something to the cancer. One mutation, in the FLT3 gene, was not present in all of the tumor cells, and they suspect that it was the last one to occur. "The final mutation may represent a tipping point that causes the cancer cells to become more dangerous," Ley says.
The team is now sequencing the genomes of additional patients with AML, and they are also planning to expand the whole-genome approach to breast and lung cancers.