Earlier this year, we reported a finding in Genome Biology that found at least two distinct scenarios of DLBCL relapse. By examining the evolution of the mutation profile between DLBCL samples collected at the initial diagnosis and later the relapse stage from the same patient, we characterized that DLBCL relapse progression followed either a linear or a divergent development fashion. Furthermore, we discovered that these two patterns could be predicted by the degree of genetic heterogeneity at diagnosis.
Recently, we expanded this study to explore the hypothesis that DNA methylation may also contribute to DLBCL disease progression and relapse. DNA methylation is one of many forms of modification to our genome. This specific modification has been linked to gene expression regulation. In addition, aberrant DNA methylation is believed to play an important role in tumor development. Using the latest sequencing technology, we interrogated 3-4 million DNA methylation sites in each sample from the pairs collected from DLBCL patients at diagnosis and relapse. We detected DNA methylation change at specific regulatory elements throughout the patient genome from disease progression to the relapse state. We further measured DNA methylation heterogeneity within each tumor, which characterized the diversity of DNA methylation patterns in the entire tumor cell population. We noticed that the diversity of DNA methylation decreased from diagnosis tumors to relapse tumors, potentially reflecting either the effect of the front line treatment or the on-going clonal selection within a tumor. More importantly, we noticed this measurement of diversity at diagnosis can predict disease progression time. We discovered that relapse-free patients displayed lower intra-tumor methylation heterogeneity at diagnosis compared to relapsed patients, providing evidence of a role of DNA methylation in DLBCL relapse.
Results from these two studies may provide physicians more powerful tools to predict relapse potential of DLBCL patients. For other on-going studies related to lymphomas, please visit websites of the Elemento Lab and the Melnick Lab.
New Developments in Lymphoma 