Genomic analysis of response to bacillus Calmette-Guérin (BCG) treatment in high-grade stage 1 bladder cancer patients.

Content Provider	Europe PMC
Author	Sanders, J. Alexa Frasier, Connor Matulay, Justin T. Steuerwald, Nury M. Zhu, Jason Grigg, Claud M. Kearns, James T. Riggs, Stephen B. Gaston, Kris E. Brouwer, Cory R. Burks, R. Tucker Hartman, Aaron L. Foureau, David M. Burgess, Earle F. Clark, Peter E.
Copyright Year	2021
Abstract	BackgroundIntravesical bacillus Calmette-Guérin (BCG) therapy is standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) but overall efficacy is low, and no reliable predictive biomarkers currently exist to refine patient selection. We performed genomic analysis on high-grade (HG) T1 NMIBCs to determine if response to therapy is predicted by certain mutational and/or expressional changes.MethodsPatients with HG T1 NMIBC treated with induction BCG were stratified by response into durable and non-durable responders. Baseline tumor samples were subjected to targeted DNA sequencing and whole-exome RNAseq. Genomic variants differing significantly between response groups were analyzed using Ingenuity Pathway Analysis (IPA) software. Variant selection was refined to target potential biomarker candidates for responsiveness to BCG.ResultsAmong 42 patients, the median follow-up was 51.7 months and 40.5% (n=17) were durable BCG responders. Deleterious mutations in the RNA sequence of JCHAIN, S100A7, CLEC2B, and ANXA10 were more common in non-durable responders. Mutations in MCL1 and MSH6 detected on targeted sequencing were more commonly found in durable responders. Of all deleterious DNA and RNA mutations identified, only MCL1 was significantly associated with longer recurrence free survival (RFS) (P=0.031).ConclusionsDifferences in the genomic profiles of HG T1 NMIBC tumors exist between those who show durable response to BCG and those who do not. Using pathway analysis, those differences imply upregulation of several interconnected inflammatory pathways among responders. Specific variants identified here, namely MCL1, are candidates for further study and, if clinically validated, may serve as useful biomarkers in the future.
ISSN	22234683
Journal	Translational Andrology and Urology
Volume Number	10
PubMed Central reference number	PMC8350238
Issue Number	7
PubMed reference number	34430403
e-ISSN	22234691
DOI	10.21037/tau-21-158
Language	English
Publisher	AME Publishing Company
Publisher Date	2021-07-01
Access Restriction	Open
Rights License	Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0. 2021 Translational Andrology and Urology. All rights reserved.
Subject Keyword	Non-muscle invasive bladder cancer (NMIBC) bacillus Calmette-Guérin (BCG) intravesical therapy genomics
Content Type	Text
Resource Type	Article
Subject	Urology Reproductive Medicine