Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use

Abstract

BackgroundIt has been suggested that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to chemotherapy. We aimed to validate these subtypes in several clinical cohorts and identify signature immunohistochemical markers that would permit simple and cost-effective classification of the disease in primary care centers.MethodsWe analyzed genomic expression profiles of bladder cancer in three cohorts of fresh frozen tumor samples: MD Anderson (n = 132), Lund (n = 308), and The Cancer Genome Atlas (TCGA) (n = 408) to validate the expression signatures of luminal and basal subtypes and relate them to clinical follow-up data. We also used an MD Anderson cohort of archival bladder tumor samples (n = 89) and a parallel tissue microarray to identify immunohistochemical markers that permitted the molecular classification of bladder cancer.FindingsBladder cancers could be assigned to two candidate intrinsic molecular subtypes referred to here as luminal and basal in all of the datasets analyzed. Luminal tumors were characterized by the expression signature similar to the intermediate/superficial layers of normal urothelium. They showed the upregulation of PPARγ target genes and the enrichment for FGFR3, ELF3, CDKN1A, and TSC1 mutations. In addition, luminal tumors were characterized by the overexpression of E-Cadherin, HER2/3, Rab-25, and Src. Basal tumors showed the expression signature similar to the basal layer of normal urothelium. They showed the upregulation of p63 target genes, the enrichment for TP53 and RB1 mutations, and overexpression of CD49, Cyclin B1, and EGFR. Survival analyses showed that the muscle-invasive basal bladder cancers were more aggressive when compared to luminal cancers. The immunohistochemical expressions of only two markers, luminal (GATA3) and basal (KRT5/6), were sufficient to identify the molecular subtypes of bladder cancer with over 90% accuracy.InterpretationThe molecular subtypes of bladder cancer have distinct clinical behaviors and sensitivities to chemotherapy, and a simple two-marker immunohistochemical classifier can be used for prognostic and therapeutic stratification.FundingU.S. National Cancer Institute and National Institute of Health.

Human Epidermal Growth Factor Receptor 2 in Non-Muscle Invasive Bladder Cancer: Issues in Assessment Methods and Its Role as Prognostic/Predictive Marker and Putative Therapeutic Target: A Comprehensive Review

“…Basal BC seems to be intrinsically aggressive and associated with advanced stage and metastases at diagnosis and, therefore, with worse survival outcomes compared with the luminal subtype [70]. Surprisingly, HER2 overexpression is a well-known characteristic feature of luminal BC [10,71]. This is apparently in contrast with the results of our study [57,58] and previous studies on the role of HER2 in BC.…”

Simple and Efficient Stratification of Invasive Bladder Cancer Patients

“…BC patients with invasive basal tumors exhibit significantly lower survival rates compared to patients suffering from invasive luminal tumors (Choi et al, 2014). This observation is convincingly proven by Dadhania et al by analysis of survival rates of BC patients in several large cohorts (Dadhania et al, 2016). …”

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

“…CIT sets included tumour cell component 9; stromal components 3, 8, and 12; and components 5 and 14, which could not be attributed to either tumour or stromal cells. The basal, luminal, p53-like, and claudin-low markers were adapted from (Dadhania et al, 2016), and the squamous, neuroendocrine, and EMT markers were manually chosen based on prior knowledge and literatures. To highlight a differential activity of each signature the raw gene expression signature scores were rank-normalized in Fig.…”

“…We inferred the relative activity of 23 candidate ‘regulator’ genes that had previously been reported as associated with bladder cancer: the steroid hormone receptors ESR1/2, AR and PGR ; the nuclear receptors PPARG , three RARs (A/B/G) , and three RXRs (A/B/G); the receptor tyrosine kinases ERBB2/3 and FGFR1/3 ; and the transcription factors FOXA1, FOXM1 , GATA3/6, HIF1A, KLF4 and STAT3 and TP63 (Breyer et al, 2016; Choi et al, 2014a; Dadhania et al, 2016; DeGraff et al, 2013; Eriksson et al, 2015; Godoy et al, 2016; Jones et al, 2016; Kardos et al, 2016; Lim et al, 2016). By ‘regulator’ we mean a gene whose product induces and/or represses a target gene set, which we call a ‘regulon’ (Castro et al, 2016a).…”