Mutations In Iron-Sulfur Cluster Proteins Are Associated With Decreased Bladder Cancer Cell Senescence And Improved Survival Outcomes.

Abstract Recent tumor genome analyses have cataloged hundreds of mutated genes, including a large population of rarely mutated genes with ill-defined roles in cancer. Here we find that, when considering the 10 genes of the iron-sulfur (Fe-S) pathway as an integrated whole, somatic mutations occur with a higher than expected frequency in 21.3% of bladder tumors. Mutations in these genes are associated with increased survival and mutational burden. Analysis of tumor gene expression highlights a relationship between these Fe-S mutations and signalling regulating proliferation and quiescence, with mutations promoting proliferative programs and abolishing maintenance of quiescence. In bladder tumor cells, we show that replication of this proliferative program, using an DYRK1A kinase inhibitor, promotes sensitivity to genotoxic agents. Furthermore, disruption of Fe-S genes ERCC2, MMS19, CIOA1, BRIP1 or POLD1 promotes cell proliferation and concomitant sensitivity to genotoxic agents. These results suggest a model in which Fe-S pathway mutations are selected due to their ability to bypass DNA damage checkpoints and drive proliferation, an aspect which simultaneously creates vulnerability to chemotherapy and resultant improvements in survival. Citation Format: Devin Patel, Fan Zheng, Michael Chen, Jason Kreisberg, Erica Silva, Trey Ideker, Kate Licon. Mutations in iron-sulfur cluster proteins are associated with decreased bladder cancer cell senescence and improved survival outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 217.