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Abstract IA23: Lessons from a rare childhood cancer syndrome on replication repair deficiency and hypermutation

In order to divide, cells need to replicate their DNA. Replication is done by DNA polymerase epsilon and delta (POLE and POLD1) and creates thousands of mistakes per each replication cycle. The major components safeguarding our genome against such mutations are the proofreading capacity of both polymerases and the mismatch repair (MMR) genes. Germline mutations in either POLE or the MMR genes result in the most aggressive childhood cancer syndromes with high penetrance of cancers during childhood with the hallmark of extreme hypermutation. Data from the International Replication Repair Deficiency (RRD) Consortium reveal that this phenomenon is not restricted to the rare cancer syndrome and affects 5% of childhood cancers throughout many tissues. Hypermutation is observed in up to 10% of recurrent childhood cancers and 20% of adult cancers. Recent data reveal that there are a variety of mutational signatures that are associated with each cause of RRD and hypermutation. These mutations can be traced to the germline or previous therapy. Furthermore, signatures are not restricted to SNV but can be observed by insertions and deletions in microsatellites. Animal models of RRD shed new light on the process of tumorigenesis and mutation progression in RRD cancers and their impact on inter- and intratumoral heterogeneity. Together, these data provide an Achilles heel to these tumors where immunotherapy and combinations can improve survival for patients with germline RRD and children with RRD hypermutant cancers. Novel biomarkers of response to immunotherapy provide insight into the patterns of immune and tumor interactions in these patients. Citation Format: Uri Y. Tabori. Lessons from a rare childhood cancer syndrome on replication repair deficiency and hypermutation [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA23.