Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites

  • Amin H. Nassar
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Renato Umeton
    3Department of Informatics, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Jaegil Kim
    5The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Kevin Lundgren
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Lauren Harshman
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Eliezer M. Van Allen
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Mark Preston
    6Department of Urology, Brigham and Women's Hospital, Boston, Massachusetts.
  • Fei Dong
    7Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
  • Joaquim Bellmunt
    8Department of Medical Oncology, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.
  • Kent W. Mouw
    9Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Toni K. Choueiri
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Guru Sonpavde
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • David J. Kwiatkowski
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

抄録

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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 &lt; 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>

収録刊行物

  • Clinical Cancer Research

    Clinical Cancer Research 25 (8), 2458-2470, 2019-04-15

    American Association for Cancer Research (AACR)

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