Prevalence and Co-Occurrence of Actionable Genomic Alterations in High-Grade Bladder Cancer

Abstract

A B S T R A C T PurposeWe sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery. Patients and MethodsAn integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing. ResultsSixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways and regulators of G 1 -S cell cycle progression. Unsupervised clustering of CNAs defined two distinct classes of bladder tumors that differed in the degree of their CNA burden. Integration of mutation and copy number analyses revealed that mutations in TP53 and RB1 were significantly more common in tumors with a high CNA burden (P Ͻ .001 and P Ͻ .003, respectively). ConclusionHigh-grade bladder cancer possesses substantial genomic heterogeneity. The majority of tumors harbor potentially tractable genomic alterations that may predict for response to target-selective agents. Given the genomic diversity of bladder cancers, optimal development of target-specific agents will require pretreatment genomic characterization.

Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology

“…Gene expression data were derived from 49 high-grade tumors from MSKCC using human HT-12 expression BeadChip arrays (Illumina) as described previously (8). The MSKCC dataset was normalized and median-centered, and the MAD was computed across samples by gene.…”

“…We first created a meta-dataset of 262 high-grade muscleinvasive tumors, curated from four publically available datasets (12,(19)(20)(21) (SI Appendix, Table S1). In parallel, an independent set of 49 high-grade tumors from Memorial Sloan-Kettering Cancer Center (MSKCC) served as a validation set (8). In both the meta-dataset and the MSKCC dataset, consensus clustering identified two groups (designated K1 and K2) as the optimal number of molecular subtypes, as defined by the criterion of subclass stability ( Fig.…”

“…The MSKCC tumor set has been previously characterized for bladder cancer-relevant genetic alterations (8). We examined the relative enrichment of these molecular events in the bladder subtypes (Fig.…”

“…For example, low-grade UCs are enriched for activating mutations in fibroblast growth factor 3 (FGFR3), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and inactivating lysine (K)-specific demethylase 6A (KDM6A) mutations, whereas high-grade, muscle-invasive tumors are enriched for tumor protein p53 (TP53) and retinoblastoma 1 (RB1) pathway alterations (3)(4)(5)(6)(7)(8)(9)(10).…”

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

“…The discovery of the molecular pathways involved in urothelial cancer recurrence and progression has allowed for the identification of potential prognostic and predictive markers [116,129,130]. It has also permitted the development of novel noninvasive detection and surveillance strategies and revealed potential therapeutic targets [131][132][133][134][135][136].…”