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

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 inFGFR3andKRAS.APOBEC3AandAPOBEC3Bexpression 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 ofAPOBEC3Bis 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.

Oncotarget. 2017 Dec 16*** epublish ***

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

Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Interdepartmental Immunobiology Center, Department of Microbiology-Immunology, Northwestern University, Chicago, IL, USA.