Mentor Name: Uri Tabori

Cancer is a genetic disease driven by somatic and/or germline DNA sequence alterations. Replicative mutations are strictly surveilled by replication repair systems, including the internal proofreading domain of DNA polymerases e and d and post-replicational mismatch repair systems. This project takes advantage of the International Replication Repair Deficiency Consortium (IRRDC) large collection of DNA sequencing data from tumors with high levels of mutations (>10 mutations per mega-bases of genomic DNA) to extract mutational signatures. By correlating these extracted signatures to clinical phenotypes, this study will aim to reveal how accumulation of specific mutation types might influence tumor development and response to therapy. Given that mutation accumulation is one of the underlying factors shaping tumor response to novel therapies such as immune-based therapies like Immune Checkpoint Blockade (ICI), these findings have the potential to not only improve understanding of tumor biology, but inform treatment options based on a deeper understanding of how DNA repair systems are compromised in oncogenesis.