Mapping the Evolution of Cancer Cells in Leukemia
Drs. Timothy Graubert (left) and Matthew Walter mapped the evolution of cancer cells in seven patients with myelodysplastic syndromes who later died of leukemia.
Using whole-genome sequencing, researchers have uncovered new clues to the genetic alterations underlying acute myeloid leukemia (AML) that arises in patients who were previously diagnosed with a myelodysplastic syndrome. Myelodysplastic syndromes develop when the bone marrow stops producing enough healthy cells, and some cases progress to what is known as secondary AML.
To identify genetic mutations driving this type of AML, researchers at the Washington University School of Medicine in St. Louis sequenced the genomes of abnormal cells (obtained from bone marrow) and normal cells (obtained from skin biopsies) from seven patients whose myelodysplastic syndrome had progressed to AML. Each patient had provided samples when they were diagnosed with a myelodysplastic syndrome and later when they were diagnosed with secondary AML.
By comparing the alterations in each sample, the researchers could track the genetic evolution of the cancer cells over time. They could also identify the cluster of cells that initially caused each cancer to develop—known as the founding clone. Then, they observed new clusters of cells, or daughter clones, that emerged.
The findings, published online March 14 in the New England Journal of Medicine, suggest that the secondary AMLs were derived from bone marrow cells carrying mutations that were present during the myelodysplastic phase of disease.
To better understand the heterogeneity in cancer cells, Dr. Castro continued, researchers will need minimally invasive techniques that can collect serial specimens, as well as new ways to extract as much information as possible from these samples.
Implications for Treatment
To develop the most promising targets, "researchers need to determine whether a particular mutation is part of the founding structure of the [cancer] or whether it occurred at a later time," Dr. Graubert explained.
The researchers identified 11 mutations in the patients' cancer cells that were later found in other patients with AML, which is an indication that they may play a role in the disease. Four of the mutations had not been implicated previously in either myelodysplastic syndromes or leukemia.
The additional mutations, however, provided the statistical power the researchers needed to track the evolution of clones over time.
A Model of Cancer
This theory has been around for years, Dr. Godley said in an interview. "But new technologies allow you to ask questions that you couldn't ask before. That's what's so exciting about these kinds of genome studies."
Another recent sequencing study—this one led by Dr. Charles Swanton of the London Research Institute—described the genetic variability within different regions of the same kidney tumor. Instead of sequencing the entire genome, the researchers analyzed the protein-coding regions, or exomes.
The new findings on tumor heterogeneity are consistent with previous work in breast cancer, she noted. For instance, her group conducted an analysis of four DNA samples from the same patient whereas another group compared tumors collected from a patient 9 years apart. Similarly, her group recently reported that, in de novo AML, when patients relapse after receiving chemotherapy, the clone that emerges is derived from a clone that was present at initial diagnosis.
New technologies allow you to ask questions that you couldn't ask before. That's what's so exciting about these kinds of genome studies. —Dr. Lucy Godley
Researchers at BGI (formerly the Beijing Genomics Institute) sequenced the exomes of 25 cells donated by an Asian man with a form of kidney cancer. Among other findings, the researchers discovered that the man did not have alterations in a gene closely associated with that disease in Western populations.
This study, published in Cell, produced interesting findings, but single-cell sequencing is not ready for clinical studies, noted Dr. Michael Dean, an investigator in NCI's Center for Cancer Research and a co-author of the study.
He added: "It is clear that, for at least some [cancer] types, we will need to use multiple samples and multiple methods of genomic analysis to develop a complete picture of a cancer that can be used to guide therapies."
Dr. Mardis agreed. "These studies are all very exciting because we're now getting to the point of being able to approach [cancer] in different ways."