Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes

Abstract

Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alterations with a heterogeneous distribution. Variant histologies in tumour tissues that have developed distinct morphological characteristics divergent from urothelial carcinoma are extreme examples of tumour heterogeneity. Ultimately, heterogeneity contributes to drug resistance and relapse after therapy, resulting in poor survival outcomes. Mutation profile differences between patients with muscle-invasive and metastatic urothelial cancer (interpatient heterogeneity) probably contribute to variability in response to chemotherapy and immunotherapy as first-line treatments. Heterogeneity can occur on multiple levels and averaging or normalizing these alterations is crucial for clinical trial and drug design to enable appropriate therapeutic targeting. Identification of the extent of heterogeneity might shape the choice of monotherapy or additional combination treatments to target different drivers and genetic events. Identification of the lethal tumour cell clones is required to improve survival of patients with urothelial carcinoma.

Fig. 1 |. Different types of heterogeneity found in bladder cancer.

Bladder tumours can vary in morphology, gene expression profile and mutations. This heterogeneity exists not only between patients (interpatient heterogeneity) but also within the same patient, where subclassifications can be made. Intratumoural heterogeneity describes variations between regions of one tumour and can be affected or caused by clonality, immune cell infiltration and the tumour microenvironment. Differences between multiple tumours and/or metastases within one patient are termed intertumoural heterogeneity. Heterogeneity can also change over time and during treatment (temporal heterogeneity). Finally, differences can also exist between tissue-based tumour markers and circulating markers (circulation heterogeneity) and can be assessed by comparing data from tumour deposits with those from liquid biopsy approaches.

Fig. 2 |. Tumour evolution with emergence of distinct tumour subtypes.

a | Schematic of the occurrence of tumour subclones over time. Genomic differences between subclones might result in different expression patterns and thereby different tumour subtypes. Chemotherapy can cause contraction of subtypes and isolation of a specific subtype, which becomes the dominant clone after chemotherapy (subtype 4 in this example). b | The fractions of different subtypes can vary over time and under the selection pressure of treatments, resulting in inconsistent subtype calling even if the entire tumour is analysed. Sampling of only parts of a tumour would be expected to further complicate consistent subtype calling.

Fig. 3 |. Variant histology of urothelial carcinoma.

Tumour heterogeneity is most pronounced at the morphological level when comparing urothelial carcinomas with variant histology. The morphological spectrum of urothelial carcinoma includes divergent differentiation, such as squamous differentiation (part a) and glandular differentiation (part b). Variant histologies of urothelial carcinoma include nested variant (part c), plasmacytoid variant (part d), micropapillary variant (part e) and sarcomatoid variant (part f). Primary tumours of non-urothelial histology can also develop in the bladder, including squamous cell carcinoma (part g), mucinous adenocarcinoma with signet ring cells (part h) and small-cell or neuroendocrine carcinoma (part i). Haematoxylin and eosin staining in all images, magnification ×50.