Role and Mechanisms of Clonal Evolution in Lymphoid Malignancies
High-throughput sequencing techniques significantly accelerated the understanding of cancer genomes and uncovered a large amount of genetic variation between patients’ tumors as well as heterogeneity within tumors of the same patients. Most recent genomics studies have uncovered novel insights into disease dynamics of lymphoid neoplasms, providing evidence of clonal evolution over time driven by selective pressures during disease initiation, progression and therapeutic intervention. These studies have increasing implications for treatment resistance and dynamic biomarker testing as will be demonstrated in this session.
Dr. Charles Mullighan will discuss the genetic heterogeneity and evolution in acute lymphocytic leukemia in which clonal evolution patterns can be interpreted in the context of Darwinian evolution of founder clones and anti-leukemic therapy. Pivotal studies revealed that specific genomic alterations that facilitate resistance may be present in major or minor subclones at initial diagnosis or are acquired after commencement of therapy. Moreover, these alterations can confer resistance in drug-specific and drug-agnostic ways. The observation that the majority of relapsed-enriched alterations are present at diagnosis or early in therapy, often as subclones, indicates that sensitive mutation detection strategies are needed to anticipate and prevent relapse.
Dr. Dan Landau will address epigenetic heterogeneity in non-Hodgkin lymphoma, focusing on chronic lymphocytic leukemia (CLL) in which genetically distinct subpopulations are commonly observed and predict future evolutionary and clinical trajectories. Similar to the case of intra-tumoral genetic diversity, intra-tumoral epigenetic diversity occurs at the level of DNA methylation, leading to massive stochastic diversification in methylation patterns. Importantly, stochastic “epimutations” impact transcription, clonal evolution and clinical outcome. To robustly differentiate “epidrivers” from the majority of random passenger DNA methylation changes, a novel statistical inference framework has been developed that accounts for the varying epimutation rate across the genome. This framework can also include histone modifications revealing a decrease in the coherence between different epigenetic marks in CLL and consistent with intra-leukemic epigenetic diversity. Moreover, Dr. Landau will discuss multi-omic single-cell sequencing techniques that allow for tracking of epimutations and inferring high-resolution lineage trees.
Dr. Sarah-Jane Dawson will discuss clinical implications and biomarkers of clonal evolution using liquid biopsy approaches. Specifically, she will focus on recent technological advances in the detection and characterization of cell-free circulating tumor DNA that provide new opportunities for treatment tailoring based on real-time monitoring of tumor evolution. Liquid biopsies provide an alternative to tissue biopsies allowing noninvasive tumor genotyping and the serial analysis of genomic changes from a simple blood test. Dr. Dawson will highlight the uses of this technology to follow disease burden and track genomic changes in patients receiving novel therapies for lymphoid malignancies. She will also discuss promises and challenges in developing these tools for clinical application.
Charles Mullighan, MBBS, MD
Dan Landau, MD, PhD
Sarah-Jane Dawson, MD, PhD
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