Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise.
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Abstract | Invasive bladder cancer, for which there have been few therapeutic advances in the past 20 years, is a significant medical problem associated with metastatic disease and frequent mortality. Although previous studies had identified many genetic alterations in invasive bladder cancer, recent genome-wide studies have provided a more comprehensive view. Here, we review those recent findings and suggest therapeutic strategies. Bladder cancer has a high mutation rate, exceeded only by lung cancer and melanoma. About 65% of all mutations are due to APOBEC-mediated mutagenesis. There is a high frequency of mutations and/or genomic amplification or deletion events that affect many of the canonical signaling pathways involved in cancer development: cell cycle, receptor tyrosine kinase, RAS, and PI-3-kinase/mTOR. In addition, mutations in chromatin-modifying genes are unusually frequent in comparison with other cancers, and mutation or amplification of transcription factors is also common. Expression clustering analyses organize bladder cancers into four principal groups, which can be characterized as luminal, immune undifferentiated, luminal immune, and basal. The four groups show markedly different expression patterns for urothelial differentiation (keratins and uroplakins) and immunity genes (CD274 and CTLA4), among others. These observations suggest numerous therapeutic opportunities, including kinase inhibitors and antibody therapies for genes in the canonical signaling pathways, histone deacetylase inhibitors and novel molecules for chromatin gene mutations, and immune therapies, which should be targeted to specific patients based on genomic profiling of their cancers. |
Year of Publication | 2015
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Journal | Clin Cancer Res
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Volume | 21
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Issue | 20
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Pages | 4514-24
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Date Published | 2015 Oct 15
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ISSN | 1078-0432
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URL | |
DOI | 10.1158/1078-0432.CCR-14-1215
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PubMed ID | 26473186
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PubMed Central ID | PMC4610178
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Grant list | P30 CA016672 / CA / NCI NIH HHS / United States
CA143883 / CA / NCI NIH HHS / United States
P30CA016672 / CA / NCI NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
P30CA125123 / CA / NCI NIH HHS / United States
U24 CA143843 / CA / NCI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
U24CA143843 / CA / NCI NIH HHS / United States
U24 CA143883 / CA / NCI NIH HHS / United States
P01CA120964 / CA / NCI NIH HHS / United States
U24 CA199461 / CA / NCI NIH HHS / United States
R21 CA191687 / CA / NCI NIH HHS / United States
RP130397 / PHS HHS / United States
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