Mutational analysis of 472 urothelial carcinoma across grades and anatomic sites.

Characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets.

Using targeted exome sequencing (n=237 genes), we analyzed the mutation spectra of 82 low-grade non-muscle-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.

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% versus 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG UC 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% versus 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (p=0.001, 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 to LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC, and occurred concurrently.

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 men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Dec 28 [Epub ahead of print]

Amin H Nassar, Renato Umeton, Jaegil Kim, Kevin Lundgren, Lauren C Harshman, Eliezer M Van Allen, Mark A Preston, Fei Dong, Joaquim Bellmunt, Kent W Mouw, Toni K Choueiri, Guru Sonpavde, David J Kwiatkowski

Medicine, Brigham and Women's Hospital., Informatics, Dana-Farber Cancer Institute., Broad Institute of MIT and Harvard., Genitourinary Oncology, Dana Farber Harvard Cancer Center., Dana-Farber Cancer Institute, Harvard Medical School., Dana-Farber Cancer Institute., Urology, Brigham and Women's Hospital., Department of Pathology, Brigham and Women's Hospital., IMIM (Hospital del Mar Research Institute)., Radiation Oncology, Brigham & Women's Hospital / Dana-Farber Cancer Institute., Department of Medical Oncology, Dana Farber Harvard Cancer Center., Division of Pulmonary Medicine, Brigham and Women's Hospital .