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. Author manuscript; available in PMC: 2024 Apr 2.
Published in final edited form as: Cancer Prev Res (Phila). 2023 Oct 2;16(10):561–570. doi: 10.1158/1940-6207.CAPR-23-0112

Figure 1. BKPyV infection as a possible cause of APOBEC-mediated mutagenesis in NMIBC.

Figure 1.

A) Several viruses were detected by RNA-seq analysis of 376 UROMOL-NMIBC tumors: BK Polyomavirus (BKPyV), Herpes Simplex Virus 2 (HSV2), Cytomegalovirus (CMV), Human papillomavirus (HPV), Herpes Simplex Virus 1 (HSV1), Human Betaherpesvirus 7 (HHV7), and Epstein-Barr Virus (EBV). Within the subset of 279 tumors with FGFR3/PIK3CA mutations, APOBEC-type driver mutations in these two genes were most common in the BKPyV-positive tumors. P-values are for Fisher’s exact test. B) Time to progression to MIBC in NMIBC patients with FGFR3 or PIK3CA mutations from the UROMOL study. Progression-free survival (PFS) was evaluated by Kaplan-Meier analysis in 279 patients with FGFR3 or PIK3CA mutations according to BKPyV status (yes/no) by RNA-seq. C) Representative IHC images demonstrating H&E and Large T antigen (LTAg) staining in one of the 5 positive NMIBC tumors; images from additional tumors are shown in Figure S1A. Marked areas are shown at a higher magnification. Arrows point to cells positive for LTAg staining (brown dots). NMIBC patient 1 is a 71-yr old never-smoking male with stage Ta, grade 1 bladder tumor with the APOBEC-type FGFR3-S249C mutation. Positive control for LTAg antibody: HeLa cells transfected with an expression construct for truncated T antigen. The table shows results for NMIBC tumors with FGFR3/PIK3CA mutations based on BKPyV status, as determined by RNA-seq or IHC-LTAg. Tumors positive for BKPyV were more likely to harbor an APOBEC-type FGFR3/PIK3CA mutation than BKPyV-negative tumors. P-values are for Fisher’s exact test. D) Variance stabilized read counts for APOBEC3A (A3A) and APOBEC3B (A3B) RNA expression corresponding to mock-infection and 1, 3, 5, and 7 days post-BKPyV infection. E) Representative coverage plots for BKPyV RNA-seq on different days post-infection in HBLAK cells (n=3) (blue), NMIBC tumors from UROMOL (green) and the only BKPyV-positive MIBC tumor (TCGA-BLCA), in which virus is integrated (red). The y-axis shows the read depth per million human reads. Positions and open reading frames within the 5-Kb BKPyV genome are shown under the X-axis. Agnoprotein – regulates viral proliferation; VP1 and VP2 - encode structural proteins for virion capsids during viral proliferation; LTAg and st - encode large and small tumor (T) antigens involved in the initiation of viral replication that causes an oncogenic transformation of the host genome.