Molecular Characterization of Neuroendocrine-like Bladder Cancer

Abstract

Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth.Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n ¼ 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n ¼ 225). A random forest model was finalized and applied to 5 validation cohorts (n ¼ 1302). Uni-and multivariable survival analyses were used to characterize clinical outcomes. Results:In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P ¼ 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P ¼ 0.001). IHC confirmed the neuronal character of these tumors.Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment. a P <0.05.Batista da Costa et al.

Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis

“…Pathological staging and clinical outcome data were not available for this cohort. (4) UTSW cohort: The UT Southwestern (UTSW) cohort consisting of 94 MIBC patients from the UT Southwestern Medical Center who underwent RC without neoadjuvant therapy [17]. In this cohort, whole transcriptome profiling was performed on RC tissue samples.…”

“…The datasets analyzed during the current study are available in the Gene Expression Omnibus repository (http://www.ncbi.nlm.nih.gov/geo/), under accession codes GSE87304 and GSE128702 [11, 17]. The TCGA RNA-seq data was available as part of the TCGA research network (http://cancergenome.nih.gov/) [12].…”

“…The TCGA RNA-seq data was available as part of the TCGA research network (http://cancergenome.nih.gov/) [12]. The PCC cohort is available for non-commercial research through a data usage agreement with the test manufacturer [17]. Requests can be made via email (partner@decipherbio.com).…”

Emerging Roles of Urine-Derived Components for the Management of Bladder Cancer: One Man’s Trash is Another Man’s Treasure

“…Recent technological advances have allowed for efficient deep molecular profiling of bladder cancer tumors to support prediction of clinical outcomes and responses to therapy 17,18,21 . Transcriptomic profiling of biopsy and cystectomy specimens has, for instance, revealed distinct molecular subtypes of bladder cancer 16,18,20,22,23 . Similar to histology, molecular classification reveals important tumor heterogeneity with coexistence of luminal and basal subtypes within the same tumor in ~30% of cases 24,29 .…”

Current Management of Localized Muscle-Invasive Bladder Cancer: A Consensus Guideline from the Genitourinary Medical Oncologists of Canada

“…There is an urgent need to develop predictive biomarkers in MIBC to improve treatment selection [278][279][280][281]. In general, molecular subtyping of MIBC reveals basal, luminal (similar to breast cancer), and neuroendocrine-like subtypes [282]. Several molecular classifications exist, and an international consensus was recently published [283].…”