1. Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites
- Author
-
Joaquim Bellmunt, David J. Kwiatkowski, Kevin Lundgren, Amin Nassar, Mark A. Preston, Guru Sonpavde, Toni K. Choueiri, Kent W. Mouw, Jaegil Kim, Renato Umeton, Lauren C. Harshman, Eliezer M. Van Allen, and Fei Dong
- Subjects
Adult ,Male ,0301 basic medicine ,APOBEC ,Urologic Neoplasms ,Cancer Research ,DNA Copy Number Variations ,DNA Mutational Analysis ,Gene mutation ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Exome Sequencing ,Biomarkers, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Exome sequencing ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Mutation ,Mutation Spectra ,Bladder cancer ,business.industry ,Gene Expression Profiling ,Genomics ,Middle Aged ,Prognosis ,medicine.disease ,Gene expression profiling ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Female ,Neoplasm Grading ,business - Abstract
Purpose: The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets. Experimental Design: Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC. Results: FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%–58% vs. 4%; 9%–22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently. Conclusions: Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.
- Published
- 2019