Schweizer Michael T, Antonarakis Emmanuel S
University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
Clin Adv Hematol Oncol. 2017 Oct;15(10):785-795.
Recent work directed toward understanding the molecular features of advanced prostate cancers has revealed a relatively high incidence of both germline and somatic alterations in genes involved in DNA damage repair (DDR). Many of these alterations likely play a critical role in the pathogenesis of more aggressive prostate cancers-leading to genomic instability and an increased probability of the development of lethal disease. However, because the ability to repair DNA damage with a high degree of fidelity is critical to an individual cell's survival, tumor cells harboring alterations in DDR pathway genes are also more susceptible to drugs that induce DNA damage or impair alternative DNA repair pathways. In addition, because the genomic instability that results from these alterations can lead to an inherently higher number of mutations than occur in cells with intact DDR pathways, patients with genomic instability may be more likely to respond to immune checkpoint inhibitors, presumably owing to a correspondingly high neoantigen burden. In this review, we discuss the emerging molecular taxonomy that is providing a framework for precision oncology initiatives aimed at developing targeted approaches for treating prostate cancer.
最近旨在了解晚期前列腺癌分子特征的研究表明，参与DNA损伤修复（DDR）的基因中，种系和体细胞改变的发生率相对较高。其中许多改变可能在侵袭性更强的前列腺癌发病机制中起关键作用，导致基因组不稳定，并增加致命疾病发生的可能性。然而，由于以高度保真度修复DNA损伤的能力对单个细胞的存活至关重要，因此携带DDR通路基因改变的肿瘤细胞也更容易受到诱导DNA损伤或损害替代DNA修复途径的药物的影响。此外，由于这些改变导致的基因组不稳定会导致比DDR通路完整的细胞中出现更多的突变，基因组不稳定的患者可能更有可能对免疫检查点抑制剂产生反应，这可能是由于相应较高的新抗原负荷。在这篇综述中，我们讨论了新兴的分子分类法，它为精准肿瘤学计划提供了一个框架，旨在开发治疗前列腺癌的靶向方法。
