Tumors are not factories for the mass production of identical cancer cells, but are, in reality, patchworks of cells with different patterns of gene mutations. A new study shows, more fully than ever before, how these mutations shift and evolve over time in chronic lymphocytic leukemia (CLL). This provides a strobe-like look at the genetic past, present, and future of CLL tumors.
Evolution may hold the key to understanding why CLL often recurs after treatment, and the key to developing better therapies. This study helps to explain why patients with seemingly similar diseases often do not derive the same benefit from therapy, why CLL recurs faster in some patients than others, and why therapy itself may speed the recurrence of the disease.
“One of the biggest challenges that patients with CLL and their physicians face is how to deal with relapse,” said study co-senior author, Catherine Wu, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts. “It’s been clear for some time that tumors are collections of different subgroups of cells, each with a particular set of gene mutations, and that, over time, some of these subgroups become more prevalent and some less. So the tumor that you initially treat can be quite different, from a genetic standpoint, from the tumor that recurs later on.”
This study, which was published in Cell (2013;152:714-726), used next-generation gene-sequencing technology to chart changes in nearly 100 samples of CLL tissue. “From there,” Wu explained, “we began exploring how these different subgroups of cells influence the effectiveness of therapy. What can these subgroups tell us about how the cancer originated and developed, and how–and how long–it will respond to treatment before relapsing?”
Genetic material in CLL tissue from 140 patients was analyzed. The analysis focused just on the sections of DNA that hold code for making cell proteins. The cells’ DNA was scoured for mutations in specific genes. For 18 patients, CLL samples taken several years apart were analyzed to track changes in the cells’ genetic makeup over time. This allowed the researchers to reconstruct, in effect, a genetic biography of a patient’s disease, identifying mutations that cropped up early or later in the disease.
Certain driver mutations—named for their ability to spur cancer formation and growth—tend to appear early in the disease’s development, while others emerge over time. The researchers discovered that the initial driver mutations tend to be unique to malignancies that originate in immune system B cells (such as CLL), while those that arose later are often found in other malignancies.
Cell subgroups were identified that became more prominent in later stages of the disease. Some subgroups of cells that had a fairly minimal presence before treatment came to predominate after treatment. Cells from patients who received chemotherapy during the years between their cell samples underwent a great deal of genetic evolution, showing marked increases in some cell subgroups and decreases in others, whereas samples from patients who did not undergo such therapy were remarkably stable.