vdj-seq-deep-sequencing-analysis-rearranged-immunoglobulin-heavy

VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma

Understanding tumor clonality is critical to understanding the mechanisms involved in tumorigenesis and disease progression. In addition, understanding ...

Weill Cornell Medical College

The Patient Safety and Quality Improvement Act offers healthcare providers an important opportunity to: Develop a patient safety evaluation system. Establish staff accountabilities, internal reporting processes, and collection/analysis protocols. Ensure legal protection for the process.

Path to safety: benefits of the 2005 Patient Safety and Quality Improvement Act.

Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas - VDJ recombination and somatic hypermutation - to address this question.

Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas.

The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here we characterize an association between disease progression and DNA methylation in diffuse large B-cell lymphoma (DLBCL). By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show that DLBCL patients exhibit heterogeneous evolution of tumour methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse-associated methylation signature converging on key pathways such as transforming growth factor-β (TGF-β) receptor activity. We also observe decreased intra-tumour methylation heterogeneity from diagnosis to relapsed tumour samples. Relapse-free patients display lower intra-tumour methylation heterogeneity at diagnosis compared with relapsed patients in an independent validation cohort. Furthermore, intra-tumour methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse.

Epigenomic evolution in diffuse large B-cell lymphomas.

Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wild-type (WT) and AID-deficient (Aicda(-/-)) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda(-/-) animals. Differentially methylated cytosines (DMCs) between GCBs and naive B cells (NBs) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID, and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells.

Article	Year
Path to safety: benefits of the 2005 Patient Safety and Quality Improvement Act. Healthcare financial management : journal of the Healthcare Financial Management Association\| PubMed ID: 16773992	2006
Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas. Genome biology\| PubMed ID: 25123191	2014
Epigenomic evolution in diffuse large B-cell lymphomas. Nature communications\| PubMed ID: 25891015	2015
DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID. Cell reports\| PubMed ID: 26365193	2015

David Redmond

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