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

// Alexander P. Glaser 1, 2 , Damiano Fantini 1, 2 , Yiduo Wang 1, 2 , Yanni Yu 1, 2 , Kalen J. Rimar 1, 2 , Joseph R. Podojil 3 , Stephen D. Miller 3 and Joshua J. Meeks 1, 2 1 Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA 2 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA 3 Interdepartmental Immunobiology Center, Department of Microbiology-Immunology, Northwestern University, Chicago, IL, USA Correspondence to: Joshua J. Meeks, email: Joshua.meeks@northwestern.edu Keywords: urinary bladder neoplasms; APOBEC deaminases; mutagenesis; DNA damage; interferon Received: September 13, 2017 Accepted: November 26, 2017 Published: December 16, 2017 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.