Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.
Nature communications. 2022 Nov 02*** epublish ***
Joshua I Warrick, Wenhuo Hu, Hironobu Yamashita, Vonn Walter, Lauren Shuman, Jenna M Craig, Lan L Gellert, Mauro A A Castro, A Gordon Robertson, Fengshen Kuo, Irina Ostrovnaya, Judy Sarungbam, Ying-Bei Chen, Anuradha Gopalan, Sahussapont J Sirintrapun, Samson W Fine, Satish K Tickoo, Kwanghee Kim, Jasmine Thomas, Nagar Karan, Sizhi Paul Gao, Timothy N Clinton, Andrew T Lenis, Timothy A Chan, Zhiyu Chen, Manisha Rao, Travis J Hollman, Yanyun Li, Nicholas D Socci, Shweta Chavan, Agnes Viale, Neeman Mohibullah, Bernard H Bochner, Eugene J Pietzak, Min Yuen Teo, Gopa Iyer, Jonathan E Rosenberg, Dean F Bajorin, Matthew Kaag, Suzanne B Merrill, Monika Joshi, Rosalyn Adam, John A Taylor, Peter E Clark, Jay D Raman, Victor E Reuter, Yu Chen, Samuel A Funt, David B Solit, David J DeGraff, Hikmat A Al-Ahmadie
Department of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA., Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA., Bioinformatics and Systems Biology Laboratory, Federal University of Parana, Curitiba, Paraná, Brazil., BC Cancer, Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Urology, Pennsylvania State University College of Medicine, Hershey, PA, USA., Department of Medicine, Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, USA., Department of Urology, Boston Children's Hospital, Boston, MA, USA., Department of Urology, University of Kansas Medical Center, Kansas City, MO, USA., Levine Cancer Institute, Atrium Health, Charlotte, NC, USA., Department of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA. ., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. .