Xiaoping Su1, Xiaofan Lu2, Sehrish Khan Bazai3,4, Eva Compérat5, Roger Mouawad6, Hui Yao1, Morgan Rouprêt7, Jean-Philippe Spano6, David Khayat6, Irwin Davidson3,4, Nizar N Tannir8, Fangrong Yan9, Gabriel G Malouf10,11,12,13. 1. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. 3. Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France. 4. Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France. 5. Department of Pathology, GRC No. 5, Predictive Onco Uro, AP-HP, Hôpital Tenon, Sorbonne University, Paris, France. 6. Department of Medical Oncology, AP-HP, Hôpital Pitié-Salpêtrière, Sorbonne University, Paris, France. 7. Department of Urology, GRC No. 5, Predictive Onco Uro, AP-HP, Hôpital Pitié-Salpêtrière, Sorbonne University, Paris, France. 8. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 9. State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. f.r.yan@163.com. 10. Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400, Illkirch, France. maloufg@igbmc.fr. 11. Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France. maloufg@igbmc.fr. 12. Department of Medical Oncology, Institut de Cancérologie de Strasbourg-Europe, Strasbourg, France. maloufg@igbmc.fr. 13. Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France. maloufg@igbmc.fr.
Abstract
BACKGROUND: Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood. RESULTS: We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes. CONCLUSIONS: Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.
BACKGROUND: Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood. RESULTS: We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes. CONCLUSIONS: Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.
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