APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

Alexander P. Glaser, Damiano Fantini, Yiduo Wang, Yanni Yu, Kalen J. Rimar, Joseph R. Podojil, Stephen D. Miller, Joshua J. Meeks*

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

APOBEC enzymes are responsible for a mutation signature (TCW > T/G) implicated in a wide variety of tumors. We explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival using sequencing data from The Cancer Genome Atlas (n = 395), Beijing Genomics Institute (n = 99), and Cancer Cell Line Encyclopedia. Tumors were split into "APOBEC-high" and "APOBEC-low" based on APOBEC enrichment. Patients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs. 18.5 months, p = 0.005). APOBEC-high tumors are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with mutation burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with IFNγ. In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response.

Original languageEnglish (US)
Pages (from-to)4537-4548
Number of pages12
JournalOncotarget
Volume9
Issue number4
DOIs
StatePublished - Jan 1 2018

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Keywords

  • APOBEC Deaminases
  • DNA damage
  • Interferon
  • Mutagenesis
  • Urinary bladder neoplasms

ASJC Scopus subject areas

  • Oncology

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