Ather M Hammad, Siddiqui Tahmeena
Dept of Surgery, Aga Khan University, Karachi, Pakistan.
Appl Clin Genet. 2012 Nov 8;5:105-10. doi: 10.2147/TACG.S28881. Print 2012.
Prostate cancer (PC) displays a strong familial link and genetic factors; genes regulating inflammation may have a pivotal role in the disease. Epigenetic changes control chromosomal integrity, gene functions, and, ultimately, carcinogenesis. The most widely studied epigenetic event in PC is aberrant DNA methylation (hypo- and hypermethylation); besides this, chromatin remodeling and micro RNA (miRNA) are other studied alterations in PC. These all lead to genomic instability and inappropriate gene expression. Causative dysfunction of histone modifying enzymes results in generic and locus-specific changes in chromatin remodeling. miRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen-receptor signaling and apoptosis. These epigenetic alterations have the potential to act as biomarkers for PC for screening and diagnosis as well as prognosis and follow-up. The variable biological potential for a newly diagnosed PC is one of the biggest challenges. The other major clinical problem is in the management of castration-resistant PC. Neuroendocrine (NE) differentiation is one of the putative explanations for the development of castration-resistant disease. Most advanced and poorly differentiated cancer does not produce prostate-specific antigen (PSA) in response to disease progression. Circulating and tissue biomarkers like chromogranin A (CgA) thus become important tools. There is the potential to use various genetic and epigenetic alterations and NE differentiation as therapeutic targets in the management of PC. However, we are still some distance from developing clinically effective tools. Valuable insights into the nature of NE differentiation in PC have been gained in the last decades, but additional understanding of its pathogenetic mechanisms is needed. This will help in devising novel therapeutic strategies to develop targeted therapies. CgA has the potential to become an important marker of advanced castration-resistant PC in cases where prostate-specific antigen can no longer be relied upon. Aberrant androgen-receptor signaling at various levels provides evidence of the importance of this pathway for the development of castration-resistant PC. Many epigenetic influences - in particular, the role of changing miRNA expression - provide valuable insights. Currently, massive sequencing efforts are underway to define important somatic genetic alterations (amplifications, deletions, point mutations, translocations) in PC, and these alterations hold great promise as prognostic markers and for predicting response to therapy.
前列腺癌（PC）呈现出很强的家族关联性和遗传因素；调控炎症的基因可能在该疾病中起关键作用。表观遗传变化控制着染色体完整性、基因功能，并最终影响致癌作用。在前列腺癌中研究最广泛的表观遗传事件是异常DNA甲基化（低甲基化和高甲基化）；除此之外，染色质重塑和微小RNA（miRNA）是前列腺癌中其他已研究的改变。这些都会导致基因组不稳定和不适当的基因表达。组蛋白修饰酶的致病性功能障碍会导致染色质重塑中的一般和位点特异性变化。miRNA失调也会促进前列腺癌发生，包括干扰雄激素受体信号传导和细胞凋亡。这些表观遗传改变有潜力作为前列腺癌的生物标志物用于筛查、诊断以及预后和随访。新诊断的前列腺癌具有的可变生物学潜能是最大挑战之一。另一个主要临床问题在于去势抵抗性前列腺癌的管理。神经内分泌（NE）分化是去势抵抗性疾病发展的一种假定解释。大多数晚期和低分化癌症不会随着疾病进展产生前列腺特异性抗原（PSA）。因此，诸如嗜铬粒蛋白A（CgA）等循环和组织生物标志物就成为重要工具。有潜力将各种遗传和表观遗传改变以及NE分化用作前列腺癌管理中的治疗靶点。然而，我们距离开发出临床有效的工具仍有一段距离。在过去几十年中已经对前列腺癌中NE分化的本质有了宝贵见解，但仍需要对其发病机制有更多了解。这将有助于设计新的治疗策略以开发靶向疗法。在无法再依赖前列腺特异性抗原的情况下，CgA有潜力成为晚期去势抵抗性前列腺癌的重要标志物。各级异常的雄激素受体信号传导证明了该途径对去势抵抗性前列腺癌发展的重要性。许多表观遗传影响——特别是不断变化的miRNA表达的作用——提供了宝贵见解。目前，正在进行大规模测序工作以确定前列腺癌中重要的体细胞遗传改变（扩增、缺失、点突变、易位），这些改变作为预后标志物和预测治疗反应具有很大前景。
