Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

Abstract Genetic networks are characterized by extensive buffering. During tumor evolution, disruption of these functional redundancies can create de novo vulnerabilities that are specific to cancer cells. In this regard, paralog genes are of particular interest, as the loss of one paralog gene can render tumor cells dependent on a remaining paralog. To systematically identify cancer-relevant paralog dependencies, we searched for candidate dependencies using CRISPR screens and publicly available loss-of-function datasets. Our analysis revealed >2,000 potential candidate dependencies, several of which were subsequently experimentally validated. We provide evidence that DNAJC15-DNAJC19, FAM50A-FAM50B and RPP25-RPP25L are novel cancer relevant paralog dependencies. Importantly, our analysis also revealed unexpected redundancies between sex chromosome genes. We show that chrX- and chrY- encoded paralogs, as exemplified by ZFX-ZFY, DDX3X-DDX3Y and EIF1AX-EIF1AY, are functionally linked so that tumor cell lines from male patients with Y-chromosome loss become exquisitely dependent on the chrX-encoded gene. We therefore propose genetic redundancies between chrX- and chrY- encoded paralogs as a general therapeutic strategy for human tumors that have lost the Y-chromosome. Citation Format: Anna Köferle, Andreas Schlattl, Alexandra Hörmann, Fiona Spreitzer, Alexandra Popa, Venu Thatikonda, Teresa Puchner, Verena Supper, Madhwesh C. Ravichandran, Sarah Oberndorfer, Corinna Wieshofer, Maja Corcokovic, Christoph Reiser, Simon Wöhrle, Johannes Popow, Mark Pearson, Barbara Mair, Ralph A. Neumüller. Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4004.