Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise.
Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise.
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DOI：
10.1158/1078-0432.ccr-14-1215
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发表时间：
2015-10-15
期刊：
影响因子：
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通讯作者：
Kwiatkowski DJ
中科院分区：
文献类型：
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作者：
Kim J;Akbani R;Creighton CJ;Lerner SP;Weinstein JN;Getz G;Kwiatkowski DJ
浸润性膀胱癌是一个与转移性疾病和高死亡率相关的重大医学问题，在过去的20年里，其治疗进展很少。虽然以前的研究已经确定了侵袭性膀胱癌的许多遗传改变，但最近的全基因组研究提供了更全面的观点。在此，我们回顾了最近的研究结果，并提出了治疗策略。膀胱癌的突变率很高，仅次于肺癌和黑色素瘤。大约65%的突变是由于apobecc介导的突变。有高频率的突变和/或基因组扩增或缺失事件，影响许多典型的信号通路参与癌症的发展：细胞周期，受体酪氨酸激酶，RAS和pi -3激酶/mTOR。此外，与其他癌症相比，染色质修饰基因的突变异常频繁，转录因子的突变或扩增也很常见。表达聚类分析将膀胱癌分为四大类，分别为腔内癌、免疫未分化癌、腔内癌和基底癌。四组在尿路上皮分化（角蛋白、尿白蛋白）和免疫基因（CD274、CTLA4）等方面表现出明显不同的表达模式。这些观察结果提示了许多治疗机会，包括针对典型信号通路基因的激酶抑制剂和抗体疗法，组蛋白去乙酰化酶抑制剂，针对染色质基因突变的新分子，以及基于癌症基因组谱的针对特定患者的免疫疗法。
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, uroplakins) and immunity genes (CD274, 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, novel molecules for chromatin gene mutations, and immune therapies, which should be targeted to specific patients based on genomic profiling of their cancers.