Researchers from the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard have harnessed the power of next-generation sequencing to analyze a large collection of leukemia tissue samples. Using whole exome sequencing (WES), the investigators screened genetic material from more than 500 samples of chronic lymphocytic leukemia (CLL) and normal tissue—identifying dozens of genetic drivers for the disease, including two genes that had previously not been linked to human cancer.
The investigators began to trace how some mutations affect the course of the disease and its susceptibility to treatment. Moreover, they started tracking the evolutionary path of CLL, as its dynamic genome spawns new groups and subgroups of tumor cells within a single patient.
“Sequencing the DNA of CLL has taught us a great deal about the genetic basis of the disease,” explained senior author Catherine Wu, M.D., physician at Dana-Farber and associate professor of medicine at Harvard Medical School. “Previous studies, however, were limited by the relatively small number of tumor tissue samples analyzed, and by the fact that those samples were taken at different stages of the treatment process, from patients treated with different drug agents.
Dr. Wu continued, stating “in our new study, we wanted to determine if analyzing tissue samples from a large, similarly-treated group of patients provides the statistical power necessary to study the disease in all its genetic diversity—to draw connections between certain mutations and the aggressiveness of the disease, and to chart the emergence of new mutations and their role in helping the disease advance. Our results demonstrate the range of insights to be gained by this approach.”
The findings from this study were published recently in Nature through an article entitled “Mutations driving CLL and their evolution in progression and relapse.”
The researchers collected tumor and normal tissue samples from 538 patients with CLL, 278 of whom had participated in a German clinical trial that helped determine the standard treatment for the disease. After WES analysis, they uncovered dozens of genetic abnormalities that may play a role in CLL, including 44 mutated genes and 11 genes that were over- or under-copied in CLL cells. Interestingly, two of the mutated genes—RPS15 and IKZF3—have not previously been associated with human cancer.
“This study also provides a vision of what the next phase of large-scale genomic sequencing efforts may look like,” noted lead author Dan Landau M.D., Ph.D., research fellow at Dana-Farber and the Broad Institute. “The growing sample size allows us to start engaging deeply with the complex interplay between different mutations found in any individual tumor, as well as reconstructs the evolutionary trajectories in which these mutations are acquired to allow the malignancy to thrive and overcome therapy.”
Another fascinating discovery was that certain gene mutations were particularly common in tumor tissue from patients who had already undergone treatment, suggesting that these mutations help the disease rebound after initial therapy. In addition, the investigators found that therapy tends to produce shorter remissions in patients whose tumors carry mutations in the genes TP53 or SF3B1.
“We found that genomic evolution after therapy is the rule rather than the exception,” Dr. Wu remarked. “Certain mutations were present in a greater number of leukemia cells within a sample after relapse, showing that these mutations, presumably, allow the tumor to persevere.”
Dr. Wu and her colleagues hope that the findings from their studies will continue the push initiated by precision medicine to help personalize cancer treatments and develop new therapeutics.
“The breadth of our findings shows what we will be able to achieve as we systematically sequence and analyze large cohorts of tumor tissue samples with defined clinical status,” stated co-senior author Gad Getz, Ph.D., director of the Cancer Genome Computational Analysis group at the Broad Institute. “Our work has enabled us to discover novel cancer genes, begin to chart the evolutionary path of CLL, and demonstrate specific mutations affect patients' response to therapy. These discoveries will form the basis for precision medicine of CLL and other tumor types.”