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

Abstract

Background: Intravesical bacillus Calmette-Guérin (BCG) therapy is standard treatment for highrisk 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. 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.Results: Among 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).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, namely MCL1, are candidates for further study and, if clinically validated, may serve as useful biomarkers in the future.

Reparameterized multiobjective control of BCG immunotherapy

“…Similarly, the gene CD 4 could contribute to the activation rate of the immune response due to BCG treatment-induced effects on effector T cells 56 . Recent research analyzing genomic profiles in bladder cancer patients receiving BCG treatment has identified differentially expressed genes and signaling pathways 57 , potentially establishing quantitative links between gene expressions and model parameters. These connections could be clarified by linking parameter functions with relevant signaling pathways.…”

Identification of Long Non-Coding RNA MIR4435-2HG as a Prognostic Biomarker in Bladder Cancer

“…The count data of GSE176178 were used as input for the “DESeq2” package to identify DEGs between BCG durable and non-durable patients [ 21 ]. In GSE176178, BCG non-durable was defined as patients with recurrence of BCa (any stage or grade) within 2 years, and BCG durable had no recurrences detected during follow-up with a disease-free interval of at least 2 years [ 22 ]. The threshold for the adjusted p -value was set as <0.05, and >0.5 for log2 fold change (logFC).…”

Characterizing molecular subtypes of high-risk nonmuscle-invasive bladder cancer in African American patients.

“…31 They found that predicted deleterious frameshift deletions of the N-terminal 1 st exon believed to be involved in protein regulation of MCL1 were significantly and disproportionally higher in durable responders and was significantly associated with recurrence free survival following BCG induction. 31 As MCL1 is an anti-apoptotic protein of the BCL2 family and its down-regulation is linked to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitization 32,33 , others hypothesized that the loss of function mutations in MCL1 may result in sensitization to TRAIL mechanisms. This may be due to a key death ligand in granulocytes following induction of BCG and release of interferon signaling particles by cancer cells resulting in the anti-neoplastic properties of BCG induction.…”

“…Sanders and Frasier et al, 2021 sought to determine whether response to bacillus Calmette-Guérin (BCG) induction therapy was associated with mutational and/or expressional changes in treatment naive high-grade T1NMIBC. 31 They performed a retrospective study, stratifying patients at their institution into non-durable responders as defined as patients with recurrence of urothelial carcinoma of the bladder (any stage or grade) during the two-year study and durable responders as defined as any recurrence of lower grade or stage than the index lesion, and subsequently performed targeted DNA sequencing and whole exome RNAseq analysis on patient high-grade T1 NMIBC prior to BCG induction. 31 They found that predicted deleterious frameshift deletions of the N-terminal 1 st exon believed to be involved in protein regulation of MCL1 were significantly and disproportionally higher in durable responders and was significantly associated with recurrence free survival following BCG induction.…”

“…31 They performed a retrospective study, stratifying patients at their institution into non-durable responders as defined as patients with recurrence of urothelial carcinoma of the bladder (any stage or grade) during the two-year study and durable responders as defined as any recurrence of lower grade or stage than the index lesion, and subsequently performed targeted DNA sequencing and whole exome RNAseq analysis on patient high-grade T1 NMIBC prior to BCG induction. 31 They found that predicted deleterious frameshift deletions of the N-terminal 1 st exon believed to be involved in protein regulation of MCL1 were significantly and disproportionally higher in durable responders and was significantly associated with recurrence free survival following BCG induction. 31 As MCL1 is an anti-apoptotic protein of the BCL2 family and its down-regulation is linked to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitization 32,33 , others hypothesized that the loss of function mutations in MCL1 may result in sensitization to TRAIL mechanisms.…”