SUO 2017: APOBEC-Mediated Mutagenesis in Urothelial Carcinoma - Associated with Improved Survival
In this abstract, the authors examine the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, immune signature, and survival. They build on the work of other groups which have begun to explore the role of APOBEC in bladder cancer. They utilized the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma dataset, which has completely sequenced data from 395 patients with bladder cancer. They used the Beijing Genomics Institute dataset of 99 patients and the Cancer Cell Line Encyclopedia as external validation of their findings. Tumors were stratified based on APOBEC mutational profile into “APOBEC-high” and “APOBEC-low.”.
In the TCGA dataset, 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). Tumors enriched for APOBEC mutagenesis 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 RAS. These were consistent across both datasets. APOBEC3A and APOBEC3B expression correlated with total mutation burden, regardless of bladder tumor molecular subtype.
From an in vitro standpoint, interestingly, expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with interferon-gamma (10 ng/mL).
Based on their results, tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response and chromatin regulatory genes, which has been previously established. This potentially provides more single-strand DNA substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response.
Again, as with all these studies, association is not implied in causation. Further work is needed to understand their exact role in the pathogenesis of bladder cancer. Additionally, whether or not these findings translate into actionable results – predictive biomarker, effective target therapy – remains to be seen.
Presented by: Alexander Paul Glaser, MD¹
Co-Authors: Damiano Fantini PhD¹, Yiduo Wang MD¹, Yanni Yu ¹, Kalen Rimar MD¹, Joseph Podojil PhD², Stephen Miller PhD² and Joshua Meeks MD PhD¹
Affiliation: ¹Northwestern University, Department of Urology, Chicago, IL; ²Northwestern University, Interdepartmental Immunobiology Center, Department of Microbiology-Immunology, Northwestern University, Chicago, IL
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, twitter: @tchandra_uromd at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC