Researchers Identify Dozens of Genetic Mutations Driving CLL and Their Evolution in Progression and Relapse
An analysis of whole-exome sequencing data from 538 patients with chronic lymphocytic leukemia (CLL), including 278 pretreatment samples collected from patients enrolled in a clinical trial, has identified 44 recurrently mutated genes and 11 recurrent somatic copy number variations. These findings included two previously unrecognized putative cancer drivers, RPS15 and IKZF3.
Through the inclusion of samples collected from the clinical trial, the researchers were able to study the impact of genetic alterations in the context of the current standard-of-care front-line therapy. The discovery is allowing researchers to chart the evolutionary path of CLL and may help inform prognosis and therapy. The study by Landau et al is published in Nature.
Study Methodology
The researchers analyzed whole-exome sequencing data from a large cohort of 538 patients with CLL, including 278 pretreatment samples collected from patients enrolled in the phase III CLL8 study, which established the combination regimen of fludarabine, cyclophosphamide, and rituximab (Rituxan) as the current standard-of-care first-line treatment for patients with CLL. The analysis enabled the researchers to identify novel genes associated with CLL, the comprehensive genetic characterization of samples from patients before exposure to contemporary treatment, and the features contributing to relapse from this therapy.
Study Findings
Through their analysis, the researchers identified 44 recurrently mutated genes and 11 recurrent somatic copy number variations, including two mutated genes, RPS15 and IKZF3, that had not previously been associated with human cancer. Their analysis also showed that 9% of the patients had mutations in the MAPK-ERK pathway and identified new types of molecular errors that allow the MYC cancer gene to become overactive.
The investigators found that BRAF mutations in CLL did not involve the canonical hotspot (V600E) seen in other malignancies but were instead clustered around the activation segment of the kinase domain, possibly indicating a different mechanism of activity. In addition, certain gene mutations were found to be especially common in tumor tissue from patients who had undergone therapy, suggesting that these mutations help the disease to rebound after initial therapy. The researchers’ analysis also found that therapy tends to produce shorter remissions in patients whose tumors carry mutations in the TP53 and SF3B1 genes.
“An important benefit of the larger cohort size is the enhanced ability to explore relationships between driver lesions based on patterns of their co-occurrence. Focusing on temporal patterns of driver acquisition—based on the distinction between clonal vs subclonal alterations in a cross-sectional analysis—we derived a temporal map for the evolutionary history of CLL. In the context of relapse after first-line fludarabine-based therapy, we note highly frequent clonal evolution, and that the future evolutionary trajectories were already anticipated in the pretreatment sample in one-third of cases with whole exome sequencing,” wrote the study authors.
“Large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome,” concluded the researchers.
Gad Getz, PhD, of the Broad Institute of MIT, Boston; Stephan Stilgenbauer, MD, of Ulm University, Germany; and Catherine J. Wu, MD, of the Broad Institute of MIT, Dana-Farber Cancer Institute, and Brigham and Women’s Hospital, Boston, are the corresponding authors of this study.
The study was funded by the National Institutes of Health, the European Research Council, the Austrian Science Fund, the American Cancer Society, the American Society of Hematology, the Burroughs Wellcome Fund Career Award for Medical Scientists, German Jose Carrerars Leukemia Foundation, the Deutsche Forschungsgemeinschaft, the Else Kröner-Fresenius-Stiftung, Virtual Helmholtz Institute, CLL Global Research Foundation, the Blavatnik Family Foundation, and the American Association for Cancer Research. For author conflict of interest disclosures, visit www.nature.com.
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