Abstract 1647: Integrative subtype analysis of muscle-invasive bladder cancer reveals subtypes that have different overall survival and respond differently to neoadjuvant chemotherapy
Authors: MO QIANXING , Li Roger , Chan Keith 
Published: August 2019

Introduction: Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease driven by accumulative alterations on DNA, epigenomics, genomics and protein expression levels. There is a clinical need to classify MIBC samples into molecular subtypes and to identify driver molecular alterations that could be targeted by precision medicine.

Methods: We performed an integrative clustering analysis of 388 TCGA MIBC samples. Each of the samples has somatic mutation, DNA copy number, methylation and gene expression data. We used Bayesian iClusterPlus method to identify integrative MIBC subtypes and subtype-specific genes and genomic features. Pathways and gene sets altered in the subtypes were identified by gene set and gene functional term enrichment analyses. To investigate the prognostic power of the subtype-specific gene expression signature, we compiled 5 more publicly available MIBC data sets and classified the samples into different subtypes using 1-nearest neighbor method. Subtype-specific overall survival was estimated by Kaplan-Meier method. Log-rank test and Cox model were used to compare the subtype-specific survival functions.

Results: We identified two integrative MIBC subtypes with distinct genomic landscapes. The top driver mutated genes included TP53, KDM6A, FGFR3, ELF3, RB1 and PIK3C2A. DNA regions containing MTAP, CDKN2A/2B, and several INFA genes were the driver altered regions. The integrative subtypes had similar gene expression pattern as the basal and differentiated subtypes reported by Mo et al., 2018 (JNCI 110(5):448-459), where a group of basal and differentiated markers were differentially expressed between the two subtypes. For this reason, we named them as basal and differentiated integrative subtypes. The basal subtypes were characterized by up-regulation of immune signaling pathways including CTLA-4, cytokine and inflammatory, NKT and JAK_STAT signaling pathways. A significant amount of the driver genes had negative correlation between methylation and gene expression. Furthermore, the subtype-specific gene expression signature was prognostic. For chemotherapy-naïve patients, the basal subtype was associated with worse overall survival. However, for patients undergone neoadjuvant chemotherapy, the basal subtype of patients had a better overall survival.

Conclusion: We identified basal and differentiated integrative subtypes of MIBC, which were characterized by distinct alterations on the DNA, epigenomics and gene expression levels. The two subtypes were associated with differentially altered pathways such as immune signaling pathways and responded differently to neoadjuvant chemotherapy. This integrative analysis has provided us a comprehensive picture of MIBC biology and revealed targetable molecular pathways for future precision therapeutics.

Citation Format: QIANXING MO, Roger Li, Keith Chan. Integrative subtype analysis of muscle-invasive bladder cancer reveals subtypes that have different overall survival and respond differently to neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1647.