Dissecting the Functional Significance of DNA Polymerase Mutations in Cancer

Abstract

DNA polymerase mutations can cause hypermutant cancers, but the mechanisms of tumorigenesis and the impact of various DNA polymerase mutations on treatment response is poorly understood. In this issue of Cancer Research, Galati and colleagues investigate the effects of cancer-associated DNA polymerase ε (Pole) mutations on tumorigenesis and response to immune checkpoint blockade. They describe novel genetically engineered mouse models harboring cancer-associated Pole mutations and examine the effects of these mutations on tumorigenesis, the tumor mutational landscape, and the tumor immune microenvironment. Integrating this information with an emerging understanding of how different tumor mutations influence the response to immunotherapy may aid in prediction, diagnosis, and treatment of Pole-mutant tumors. See related article by Galati et al., p. 5606

Immune Checkpoint Blockade Delays Cancer and Extends Survival in Murine DNA Polymerase Mutator Syndromes

“…Patients with Pole mutations have been reported to be prone to colorectal and endometrial cancers [46]. Introducing Pole exonuclease domain mutations in C57BL6 mice caused them to mainly develop lymphomas and some intestinal and lung tumors shown in this study and others [36, 47]. The types of tumors formed appear to be influenced by the mouse background as Pole mutations leading to endometrial tumors with high TMB have been reported [23].…”

Revisión bibliográfica: Función e importancia de las ADN polimerasas

“…Familia B Con respecto a los miembros de la familia B, los organismos eucariotas poseen cuatro polimerasas, siendo estas: alfa (Pol α), delta (Pol δ), épsilon (Pol ε) y zeta (PolZ). Pol δ y Pol ε son consideradas polimerasas de alta fidelidad, por su capacidad de corrección de errores exonucleasa 3'-5' (3,8). Carrera de Medicina.…”

“…Teniendo como ejemplo la Polδ, encontrándose presente en eucariotas unicelulares y multicelulares; participando en la replicación y reparación de ADN (32). Se ha demostrado que el gen que codifica para dicha enzima se encuentra sobre expresado en células cancerígenas (3,30,33). De igual manera, el gen que codifica para Polϴ se ha visto sobre expresado en células tumorales de cáncer de pulmón, seno, ovario, estómago y colorrectal (3,30,34).…”

“…Se ha demostrado que el gen que codifica para dicha enzima se encuentra sobre expresado en células cancerígenas (3,30,33). De igual manera, el gen que codifica para Polϴ se ha visto sobre expresado en células tumorales de cáncer de pulmón, seno, ovario, estómago y colorrectal (3,30,34).…”