The evolving genomic landscape of urothelial carcinoma

Key Points

  • Urothelial carcinoma has a high degree of mutational heterogeneity and a high frequency of somatic mutations compared with other solid tumours

  • The APOBEC family of enzymes, including APOBEC3B, are a source of hypermutation in urothelial carcinoma, resulting in a high frequency of TpC>T or G mutations

  • Urothelial carcinoma also has a high number of epigenetic changes and a high frequency of mutations in chromatin remodelling genes

  • Mutations in FGFR3 and KDM6A are more common in non-muscle-invasive bladder cancer (NMIBC) than muscle-invasive bladder cancer (MIBC), whereas mutations in PT53 and MLL2 are more common in MIBC

  • Upper tract urothelial carcinoma tumours seem to be genetically similar to urothelial carcinoma of the bladder, but further study with more samples is needed

  • The molecular pathways discovered in multiple high-throughput analyses of urothelial carcinoma might be therapeutically targetable in future clinical studies

Abstract

Survival of patients with urothelial carcinoma (including bladder cancer and upper tract urothelial carcinoma) is limited by our current approaches to staging, surgery, and chemotherapy. Large-scale, next-generation sequencing collaborations, such as The Cancer Genome Atlas, have already identified drivers and vulnerabilities of urothelial carcinoma. This disease has a high degree of mutational heterogeneity and a high frequency of somatic mutations compared with other solid tumours, potentially resulting in an increased neoantigen burden. Mutational heterogeneity is mediated by multiple factors including the apolipoprotein B mRNA editing enzyme catalytic polypeptide family of enzymes, smoking exposure, viral integrations, and intragene and intergene fusion proteins. The mutational landscape of urothelial carcinoma, including specific mutations in pathways and driver genes, such as FGFR3, ERBB2, PIK3CA, TP53, and STAG2, affects tumour aggressiveness and response to therapy. The next generation of therapies for urothelial carcinoma will be based on patient-specific targetable mutations found in individual tumours. This personalized-medicine approach to urothelial carcinoma has already resulted in unique clinical trial design and has the potential to improve patient outcomes and survival.

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Figure 1: Number of somatic mutation rates across The Cancer Genome Atlas (TCGA) projects.
Figure 2: APOBEC-mediated mutations.
Figure 3: Association of total mutation load and apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC)3B expression level.
Figure 4: Illustration of an FGFR3–TACC3 fusion protein described in The Cancer Genome Atlas.
Figure 5: HPV16 insertion into BCL2L1 on chromosome 20 described in The Cancer Genome Atlas.
Figure 6: Common signalling mechanisms, pathways, frequency of mutations, and copy number alterations (CNA) in bladder cancer.

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Acknowledgements

The results shown here are in part based upon data generated by the TCGA Research Network:https://cancergenome.nih.gov. J.J.M. is funded by a Veterans Health Administration Merit grant BX0033692-01

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A.P.G., D.F., E.M.S. and J.J.M. researched data for the article. A.P.G., D.F. and J.J.M. made substantial contributions to discussion of content and wrote the manuscript and all authors reviewed and edited the article before submisission.

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Correspondence to Joshua J. Meeks.

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TCGA Research Network

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Glossary

Epigenetic

Any non-nucleotide alteration that effects gene expression by altering DNA. This can include methylation, histone modification, or chromatin condensation.

Next-generation sequencing

(NGS). Refers to multiple high-throughput, scalable technologies used to sequence DNA and RNA.

The Cancer Genome Atlas

(TCGA). A collaboration between the National Cancer Institute and National Human Genome Research Institute to evaluate the cancer mutations of 33 different tumours.

Muscle-invasive bladder cancer

(MIBC). Cancers that invade the muscle (Stage ≥T2).

Non-muscle-invasive bladder cancer

(NMIBC). Tumours that do not invade the muscle (Stage Tis, Ta, T1).

Apolipoprotein B mRNA editing enzyme catalytic polypeptide

(APOBEC). An enzyme family that is involved in single-stranded DNA C>U deamination that cause a hypermutation phenotype.

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Glaser, A., Fantini, D., Shilatifard, A. et al. The evolving genomic landscape of urothelial carcinoma. Nat Rev Urol 14, 215–229 (2017). https://doi.org/10.1038/nrurol.2017.11

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