Most of the hundreds of mutations found in acute myeloid leukemia (AML) genomes occur randomly as part of the aging process, independent of the development of cancer, researchers have found.
After sequencing the genomes of 200 persons with AML in an effort to understand the mutations at the root of the disease, Daniel Link, MD, and colleagues found that the leukemia cells of each patient held hundreds of mutations. Although scientists have long believed that all the mutations in a cancer cell are likely to be important for the disease to progress, “We knew all of these mutations couldn’t be important,” recounted Link in a statement issued by the Washington University Schoolof Medicine in St. Louis, Missouri, where he is a professor ofmedicine. “It didn’t make any sense to us that so many mutations were present in all the cells in the tumor.”
Upon further investigation involving the isolation of blood stem cells from healthy people ranging from newborns to a man in his 70s, Link’s team discovered that each of the approximately 10,000 blood stem cells in a person’s bone marrow acquires about 10 mutations over the course of a year, so that by age 50 years, nearly 500 mutations have accrued in every blood stem cell. These random background mutations occur during cell division and are unrelated to cancer.
“Mutations are known to develop in cells as we age, but no one had any idea how many mutations occur in blood stem cells and how frequently they develop,” Link pointed out. “Our DNA can tolerate a huge number of these hits without any negative consequences, but if a cancer-initiating event occurs in one of these stem cells, it captures the genetic history of that cell, including the earlier mutations, and drives leukemia to develop.”
In many cases, only one or two additional, cooperating mutations are needed to generate the malignancy. This knowledge can help researchers zero in on the few mutations that may eventually respond to targeted therapy.
These findings, which were published in the journal Cell (2012;150:264-278), help to explain why leukemia becomes more common with age (AML is relatively uncommon until about the age of 60 years), and could explain the large numbers of mutations found in breast, lung, and other cancers.