Chromosomal translocations arising from aberrant repair of multiple DNA double-strand breaks (DSBs) are a defining characteristic of many cancers. DSBs are an essential part of physiological processes in antibody-producing B cells. The B cell environment is poised to generate genome instability leading to translocations relevant to the pathology of blood cancers. These are a diverse set of cancers, but limited data from under-represented groups have pointed to health disparities associated with each. We focus on the DSBs that occur in developing B cells and propose the most likely mechanism behind the formation of translocations. We also highlight specific cancers in which these rearrangements occur and address the growing concern of health disparities associated with them.

Activation-induced cytidine deaminase (AID) is a B cell-specific mutator required for antibody diversification. However, it is also implicated in the etiology of several B cell malignancies. Evaluating the AID-induced mutation load in patients at-risk for certain blood cancers is critical in assessing disease severity and treatment options. We have developed a digital PCR (dPCR) assay that allows us to quantify mutations resulting from AID modification or DNA double-strand break (DSB) formation and repair at sites known to be prone to DSBs. Implementation of this assay shows that increased AID levels in immature B cells increase genome instability at loci linked to chromosomal translocation formation. This includes the CRLF2 locus that is often involved in translocations associated with a subtype of acute lymphoblastic leukemia (ALL) that disproportionately affects Hispanics, particularly those with Latin American ancestry. Using dPCR, we characterize the CRLF2 locus in B cell-derived genomic DNA from both Hispanic ALL patients and healthy Hispanic donors and found increased mutations in both, suggesting that vulnerability to DNA damage at CRLF2 may be driving this health disparity. Our ability to detect and quantify these mutations will potentiate future risk identification, early detection of cancers, and reduction of associated cancer health disparities.