Sequencing Entire Genomes Produces Useful Evidence Regarding Cancer Evolution and DNA Damage from Ch
Sequencing entire genomes is increasingly possible, cheaper, and faster. And, the results really can produce meaningful information. ScienceDaily makes the point by highlighting this new paper from Nature on whole genome sequencing of persons with AML – a form of leukemia. The overall conclusion of the study supports the long held but unproven view that chemotherapy causes DNA damage that can play a role in the recurrence of the disease. To gather the evidence, the team from Washington University in St. Louis used whole genome sequencing to compare entire DNA sequences of tumors before and after relapse.
"The mutations in AML patients who have relapsed are different from those present in the primary tumor, and they are more likely to have a telltale signature of DNA damage," says senior author John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine and chief of the division of oncology. "This suggests that mutations in the relapse cells are influenced by the chemotherapy drugs the patients receive." Chemotherapy is known to damage the DNA of both cancer cells and healthy cells. But until now, scientists have had little direct evidence to suggest that chemotherapy itself helps shape the evolution of cancer cells and may contribute to disease recurrence. The researchers suspect this phenomenon is not unique to AML and may occur in other cancers as well.”
For the current study, scientists at Washington University’s Genome Institute sequenced the genomes — the entire DNA — of cancer cells before and after relapse in eight patients with AML and compared the genetic sequences to healthy cells from the same patients. The data essentially allowed them to map the evolution of cancer cells in each patient.
All the patients received cytarabine and an anthracycline drug to induce remission plus additional chemotherapy in an attempt to keep the cancer from returning. Using technology developed at the Genome Institute, the researchers isolated the DNA segments that contained every mutation in the samples of cancer cells and sequenced those regions nearly 600 times each, far more than the usual 30 times each, which substantially increased the statistical accuracy of the results.
Sequencing the entire genomes of the cancer cells was essential to the researchers’ discoveries. Most of the mutations in the relapse samples occurred in the regions of the genome that don’t include genes and would have been missed if the researchers had sequenced only a portion of the patients’ DNA.
"If we only look at the genes, we typically find a total of 10 to 25 mutations in each patient with AML," says lead author and Genome Institute scientist Li Ding, PhD, research assistant professor of genetics. "That’s not enough to see significant changes in the mutational patterns of the primary tumor cells versus those in the relapsed cells. Whole-genome sequencing identifies hundreds of mutations in each patient, which provides the resolution and confidence necessary for us to dig deeper to understand how cancer evolves."