Somatic POLE exonuclease domain mutations in endometrial cancer : Insights into the biology of POLE-mutant tumors

Abstract

Somatic mutations in the proofreading domain of DNA

polymerase epsilon denote a distinct molecular subgroup of endometrial

cancer, characterized by an exceptionally high mutational burden. Despite

this so-called ‘ultramutated’ phenotype, POLE-mutant endometrial cancers have an excellent prognosis with very few recurrences. This thesis provides insights into somatic POLE exonuclease domain mutations in endometrial cancer and especially into the underlying mechanisms by which these POLE mutations contribute to the favorable clinical outcome. Studies in this thesis focus on the immune response in POLE-mutant endometrial cancers and show that these tumors are characterized by an intratumoral T cell response. This response correlates with an enrichment of neo-epitopes, providing a plausible mechanisms for the excellent prognosis of these cancers. We demonstrate that increased sensitivity to adjuvant treatment cannot explain the good clinical outcome. Furthermore, we show that somatic POLE mutations are early, and probably initiating events in endometrial and colorectal carcinogenesis. These insights provide a deeper understanding of the molecular mechanisms underlying this group of endometrial cancers and may facilitate the implementation of POLE mutation screening in routine clinical practice. This would be an important step towards a more tailored treatment approach in endometrial cancer.