To find genetic mutations involved in acute myeloid leukemia (AML), researchers have sequenced the genomes of normal cells and cancer cells from a woman with the disease. They identified 10 mutations that were found only in the cancer cells, including 8 affecting genes not previously associated with AML. Further research is needed to determine what role, if any, the mutations play in the disease, the study authors said.

The study marks the first time that researchers have decoded the entire DNA sequence of a person with cancer. Researchers at the Washington University School of Medicine in St. Louis launched the study after targeted-sequencing approaches had largely failed to produce new insights into the genetics of AML, a cancer of white blood cells that has been difficult both to study and to treat.

With "next-generation" whole-genome sequencing tools becoming available and costs dropping, the team undertook a side-by-side comparison of normal and cancer genomes from the same patient. The researchers detected mutations that would have been missed by other methods, such as Sanger sequencing.

The results demonstrate the power of sequencing entire genomes to discover novel cancer-related mutations, said Dr. Richard K. Wilson, who directs the Genome Sequencing Center at Washington University.

Reporting their results in the November 6 Nature, the researchers caution that hundreds, if not thousands, more normal and AML genomes will need to be sequenced to put the findings in context and advance the development of clinical tools.

"Sequencing one cancer genome doesn't tell you how to treat patients," noted lead investigator Dr. Timothy J. Ley. "The real significance of this study is that we've learned how to sequence the human genome to find all of the mutations in the genes. This has never been done before, and technologically it's extremely challenging."

Dr. Brian Druker, who led the development of imatinib (Gleevec) for another type of leukemia, called the study a "tour-de-force." The discovery of mutations in a small number of genes that no one predicted sets the stage for large-scale sequencing of cancer genomes, he said in a statement. Dr. Druker directs the Oregon Health and Science University Cancer Institute and was not involved in the research.

The cells were from a woman who developed AML in her 50s and died of the disease after a relapse. (She was also the first woman to have her genome sequence published.) Nine of the 10 gene mutations were present in all of the cancer cells examined, and this suggests that "they are all likely to be relevant," said Dr. Ley.

The mutations were also present when the disease recurred. "It's reasonably clear to us that basically the same tumor recurred in this patient," Dr. Ley noted. A population of cells in the original tumor may have survived the initial treatment.

The 8 newly identified mutations appear to be rare, as they were not detected in 187 additional patients.

The current analysis was limited to genes, but the investigators are now focusing on other parts of the genome. Genes make up a tiny fraction of the genome, and there is growing evidence that other regions which harbor elements that regulate genes are important in cancer.

As with all genome projects, generating and analyzing the sequence are really just the beginning. But having a complete sequence ensures that in the future, as more is learned about how the genome functions, researchers can go back and ask new questions, said co-lead investigator Dr. Elaine Mardis.

The investigators are sequencing the genome of a second patient with AML, a man who has been in remission, and they have plans to start sequencing a third patient.

The hope is that integrating information about the biological pathways involved in AML will start to benefit patients, perhaps through the development of diagnostic and prognostic tools and eventually targeted therapies.

"At the end of the day the purpose of this research is to improve patient care," said Dr. Mardis.  

—Edward R. Winstead