Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset

Abstract

Context Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. Objective The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. Evidence acquisition We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA’s bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. Evidence synthesis The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. Conclusions The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. Patient summary Our observation showed that some of subtype-enriched mutations and copy number variations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer.

The consensus molecular classification of muscle-invasive bladder cancer

“…For Ba/Sq tumours, as shown previously 26 , the most frequently mutated genes were TP53 (P=5.8x10 -4 ), NFE2L2 (P=0.002) and RB1 (P=0.002). Aggregated mutation data revealed that 58% (134/232, P=0.009) and 20% (43/224, P=0.007) of Ba/Sq tumours contained mutations in TP53 and RB1, respectively.…”

Immunohistochemistry-based taxonomical classification of bladder cancer predicts response to neoadjuvant chemotherapy

“…ERCC2 mutation prevalence is similar in BASQ-like and non-BASQ-like tumours (8). RB1 mutations -but not deletions -are significantly more common in BASQ-like than in urothelial tumours.…”

“…However, deletions are more common in the Lund "genomically unstable" subgroup. There is insufficient data to indicate whether ATM and FANCC alterations are enriched in any taxonomical types (8,10), suggesting that combined mutational analysis and tumour subtyping could increase the ability to predict NAC response.…”

“…A better understanding of the molecular heterogeneity of UBC (8-10) has enabled classifying MIBC patients according to molecular profiles. Several groups have proposed classifications of all (11), NMIBC (12) or MIBC (8)(9)(10)13,14) tumours according to their transcriptome. Common to them is the identification of a tumour subgroup resembling basal-like breast cancers; there is consensus that Basal/Squamous-like (BASQ) tumours can be defined by ¡ KRT5/6 and KRT14 expression and lack of GATA3 and FOXA1 (15).…”

Pre‐diagnostic circulating insulin‐like growth factor‐I and bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition

“…We found no association with either aggressive or non‐aggressive cancers and no significant heterogeneity in the association by tumour aggressiveness. While genetic studies have suggested that bladder cancer can be classified into more specific molecular subtypes, we were not able to examine this due to lack of data on tumour genotype.…”