Somatic hypermutation (SHM) is an essential mechanism for the development of high-affinity antibodies. SHM occurs in germinal center B cells targeting antibody-coding immunoglobulin (Ig) genes to increase the affinity of antibodies towards the recognized antigens. SHM is catalyzed by the enzyme AID (activation-induced cytidine deaminase) which is a powerful mutator and is linked to the formation of several types of malignancies. Despite the importance of SHM for efficient immune response, it is a severe threat to genome integrity if targeted outside Ig loci. SHM targeting mechanisms are still largely unknown and even less is known about SHM off-targeting. Cis-acting elements in Ig loci, termed mutation enhancers, have been found to target SHM to Ig genes. In this thesis work, it was investigated if SHM off-targeting relies on mutation enhancers similar to SHM on-targeting.

The SHM targeting activity of viral and endogenic elements was tested and the changes this activity causes to neighboring genes was determined. SHM targeting activity from polyomavirus (SV40, JCPyV and MCPyV) regulatory regions was established and AID/APOBEC-induced mutation accumulation to viral LT -area was found. A subset of these mutations caused STOP-codon formation and in the context of SV40, truncated LT-protein expression linked to AID mutagenesis was observed. In the context of MCPyV, expression of truncated LT is tightly linked to formation of Merkel cell carcinoma. Whether truncated LT is relevant for SV40-induced tumorigenesis remains to be elucidated. SHM targeting activity was also found in the BCL6 enhancer region. Preliminary evidence suggests that inserting a strong SHM targeting element into the BCL6 enhancer region might increase mutation accumulation to the BCL6 gene linked to lymphomagenesis, but this finding requires further confirmation.

In conclusion, SHM targeting activity was established outside Ig loci in viral and endogenic contexts. The results of this work revealed that SHM targeting activity is a more widespread feature than previously anticipated. SHM off-targeting activity of proto-oncogenic enhancers can predispose to malignant transformation given that the AID enzyme is expressed at some stage of tumor evolution.