Final Report Summary - LYMPHOONCOGENOMICS (Deciphering the Oncogenic Lesions and Pathways of B and T Cell Cancers)
During the execution of this project, we made the surprising discovery that the RAG nuclease plays major roles in repairing self-generated DNA double-strand breaks. This function is redundant with the ubiquitous DNA repair machinery and is crucial to maintain genome stability during antigen receptor diversification, preventing the onset of B and T cell lymphomas. Our results also provide a mechanistic explanation for the normal V(D)J recombination observed in some DNA repair-deficient animals (and humans) and globally reveal unanticipated major roles for both DNA repair as well as the RAG complex in V(D)J recombination and genome stabilization.
We have also generated unique mouse models of genomic instability and lymphoid cancers and have developed next generation sequencing-analytical tools to identify somatic mutations, including structural rearrangements, point mutations and copy number variations in lymphoid cancers. Our results show that aberrant recombination activities during antigen receptor gene assembly lead to accelerated lymphomagenesis associated with an increased number of structural variations initiated at both antigen receptor loci and ectopic locations. These structural variations include translocations, deletions, duplications and inversions that were often clustered together, associated with high copy number changes and lead changes in expression of potentially oncogenic genes. Additionally, integrative analysis of whole-genome and transcriptome sequencing data identified known cancer genes to be recurrently affected by both structural variations and point mutations. We have also identified additional suspected cancer driver genes that are found in both mouse lymphoma models and some human hematological cancers. In summary, our work has allowed us to delineate RAG-dependent versus RAG-independent processes underlying mutations of known and suspected cancer driver genes in T-cell lymphomas and more generally provides a novel experimental platform to decipher the mechanisms underlying the appearance of somatic mutations in lymphoid cancers.