Genomic heterogeneity as a barrier to precision oncology in urothelial cancer.

Precision oncology relies on the accurate molecular characterization of individual patients with cancer at the time of treatment initiation. However, tumor molecular profiles are not static, and cancers continually evolve because of ongoing mutagenesis and clonal selection. Here, we performed genomic analyses of primary tumors, metastases, and plasma collected from individual patients to define the concordance of actionable genomic alterations and to identify drivers of metastatic disease progression. We observed a high degree of discordance of actionable genomic alterations, with 23% discordant between primary and metastatic disease sites. Among chromatin-modifying genes, ARID1A mutations, when discordant, were exclusive to the metastatic tumor samples. Our findings indicate that the high degree of lesion-to-lesion genomic heterogeneity may be a barrier to precision oncology approaches for bladder cancer and that circulating tumor DNA profiling may be preferred to tumor sequencing for a subset of patients.

Cell reports. 2022 Dec 20 [Epub]

Timothy N Clinton, Ziyu Chen, Hannah Wise, Andrew T Lenis, Shweta Chavan, Mark T A Donoghue, Nima Almassi, Carissa E Chu, Shawn Dason, Pavitra Rao, James A Rodrigues, Naresh B Vasani, Fourat Ridouani, Jonathan E Rosenberg, Dean F Bajorin, Min Yuen Teo, Bernard H Bochner, Michael F Berger, Irina Ostrovnaya, Eugene J Pietzak, Gopa Iyer, Sizhi Paul Gao, Wenhuo Hu, Hikmat A Al-Ahmadie, David B Solit

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Physiology, Biophysics and Systems Biology Program, Weill Cornell Medicine, New York, NY 10065, USA., Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Interventional Radiology, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: .