Deep sequencing studies have provided new insights into the genetic changes that allow previously treated acute myeloid leukemia (AML) to relapse and resist further treatment. A Washington University, St. Louis team led by researchers at The Genomics Institute, has identified two different clonal evolution patterns associated with relapse in AML, and a number of novel, recurrently mutated genes.
They report their studies in Nature in a paper titled “Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.”
Most patients with AML die from progressive disease after relapse, which is associated with mutational changes. To investigate such changes further and evaluate the contribution of clonal evolution to relapse, the authors carried out whole-genome sequencing of primary tumor-relapse pairs and matched skin samples from eight AML patients. All received treatment using cytarabine and anthracycline for induction therapy, and additional cytotoxic chemotherapy for consolidation treatment.
Of the 19 relapse-specific genes identified, many had previously been associated with AML, but novel, recurring mutations were also found in genes including in WAC, SMC3, DIS3, DDX41, and DAXX. Critically, the results also identified two general patterns of clonal evolution characteristic of AML relapse. In the first case, the dominant clone in the primary tumor gained additional mutations and evolved into the relapse clone. This indicates that treatment for the primary cancer therapy wasn’t completely effective, the researchers note, perhaps because the patients couldn’t tolerate consolidation therapy, or may have carried mutations in their founding clones (or had germline variations) that made the primary tumor more resistant to treatment.
In the second scenario a minor subclone carrying the majority, but not all, of the primary tumor mutations survived treatment, gained mutations, and expanded at relapse. This suggests that specific mutations in a key subclone might contribute to chemotherapy resistance, or perhaps the mutations important for relapse were acquired during tumor evolution, or both.
In fact, each tumor analyzed displayed clear evidence of clonal evolution at relapse and also a higher frequency of transversions that were likely induced by DNA damage from chemotherapy, the authors write. This aspect of their data also highlights the potential that chemotherapy might contribute to relapse by generating new mutations in the founding clone or one of its subclones, which then can undergo selection and clonal expansion.
“The AML genome in an individual patient is clearly a ‘moving target’,” the authors conclude. Eradication of the founding clone and all of its subclones will be required to achieve cures.