Abstract B014: KDM4B mutations in human cancers

Abstract

Abstract Homology-dependent-repair (HDR) is an essential process for the error-free correction of double-strand-breaks (DSBs). The histone demethylase KDM4B plays a role in the HDR repair process, wherein its H3K9 demethylase activity aids recruitment of repair factors such as the ATM checkpoint activator and KAT5 histone acetyltransferase and remodeler to the break site. Inhibition of KDM4B has been shown to disrupt the recruitment of ATM, and KAT5, affecting other downstream HDR factors and leading to widespread unrepaired DNA damage. Both over- and under-expression of KDM4B have implications for cancer severity, and changes in KDM4B expression have been shown to affect the expression of other oncogenes outside of the HDR pathway. We performed a pan-cancer analysis of the effects of KDM4B alterations in human cancers using data from the Catalogue of Somatic Mutations in Cancers (COSMIC). We find that KDM4B mutations occur in nearly every cancer. Further, there is a tendency of co-occurring mutations between KDM4B and several HDR genes the most significant being BRCA2. Machine learning tools did not predict any of the observed KDM4B mutations to be drivers. Our data suggests that although KDM4B does not display a driver phenotype it contributes to the destabilization of DNA damage repair machinery that causes cellular transformation and immortalization. Citation Format: Wesley A. Bush, Ruben C. Petreaca. KDM4B mutations in human cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B014.