GSE176178
Genomic Analysis of Response to Bacillus Calmette-Guerin (BCG) Treatment in High-Grade Stage 1 Bladder Cancer Patients
Background: Intravesical 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. Methods: Patients with HG T1 NMIBC treated with induction BCG were stratified by response into durable and non-durable responders. Tumor samples were subjected to whole-exome RNA sequencing. Gene expression and variant analysis were performed on RNA sequencing to identify changes between BCG durable responders and those that did not respond. Results: Differentially expressed genes in durable responders were input into IPA and identified associated immune related pathways: MIF-mediated Glucocorticoid Regulation, MIF Regulation of Innate Immunity, and p38 MAPK Signaling. The differentially expressed genes were crossed with RNAseq variant analysis to identify genes that had significant changes in both. This analysis identified JCHAIN, S100A7, CLECB, and ANXA10 genes that had snps in non-durable responders vs durable responders and also had significant change in gene expression between these two groups. Conclusions: Differences 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 are candidates for further study and, if clinically validated, may serve as useful biomarkers in the future. Overall design: RNA sequencing of stage 1 bladder cancer tumor samples in patients treated with BCG treatment.