TY - JOUR
T1 - Invasive bladder cancer
T2 - Genomic insights and therapeutic promise
AU - Kim, Jaegil
AU - Akbani, Rehan
AU - Creighton, Chad J.
AU - Lerner, Seth P.
AU - Weinstein, John N.
AU - Getz, Gad
AU - Kwiatkowski, David J.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/10/15
Y1 - 2015/10/15
N2 - 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 APOBECmediated 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.
AB - 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 APOBECmediated 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.
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U2 - 10.1158/1078-0432.CCR-14-1215
DO - 10.1158/1078-0432.CCR-14-1215
M3 - Review article
C2 - 26473186
AN - SCOPUS:84945577534
SN - 1078-0432
VL - 21
SP - 4514
EP - 4524
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -