Katharina Wimmer is Associate Professor at the Institute of Human Genetics at the Medical University Innsbruck, Austria. She is a European registered Clinical Laboratory Geneticist and supervises the diagnostics lab of the hereditary cancer genetics unit at this institute. She serves as national coordinator of the ERN GENTURIS in Austria. One of her research focusses is constitutional mismatch repair deficiency (CMMRD) and more broadly constitutive replication error repair (RER) deficiencies. She co-founded the European consortium “Care for CRMMRD”, which aims at improving diagnosis and management of children/young adults with this syndrome.
High DNA replication fidelity before cell division is achieved by the base selectivity intrinsic to the replication DNA polymerases ε and δ (POLε, POLδ), as well as their 3' to 5' exonuclease proofreading activity. Post-replication, the DNA mismatch repair (MMR) system corrects errors that escape proofreading. Compromised polymerase proofreading and MMR deficiency is observed in a variety of tumor types, and sometimes even simultaneously. Both RER defects increase mutation rates resulting in cancers with exceptionally high tumor mutational burden (TMB) and distinct mutational signatures. Whilst typically observed somatically in neoplastic cells, both defects have also been described as very rare constitutional conditions that cause distinct cancer predisposition syndromes.
This webinar will (i) render an overview on the cellular effects and the therapeutic implications of RER deficiency in tumors and (ii) our current knowledge on phenotypic differences and overlap between constitutional polymerase proofreading deficiency and CMMRD. (iii) Differences between somatic and germline POLE (POLε) and POLD1 (POLδ) pathogenic variants as well as strategies and challenges of POLE and POLD1 variant classification will be discussed.