Mikhaylenko D S, Efremov G D, Sivkov A V, Zaletaev D V
Lopatkin Institute of Urology and Interventional Radiology, National Medical Radiological Research Center, Ministry of Health, Moscow, 105425 Russia.
Research Centre for Medical Genetics, Moscow, 115478 Russia.
Mol Biol (Mosk). 2016 Jan-Feb;50(1):34-43. doi: 10.7868/S002689841506018X.
Progression of malignant tumors is largely due to clonal evolution of the primary tumor, clones acquiring different sets of molecular genetic lesions. Lesions can confer a selective advantage in proliferation rate or metastasis on the tumor cell population, especially if developing resistance to anticancer therapy. Prostate cancer (PCa) provides an illustrative example of clinically significant clonal evolution. The review considers the genetic alterations that occur in primary PCa and the mechanism whereby hormone-refractory PCa develops on hormone therapy, including mutations and alternative splicing of the androgen receptor gene (AR) and intratumoral androgen synthesis. Certain molecular genetic lesions determine resistance to new generation inhibitors (AR mutations that block the antagonist effect or allow other hormones to activate the receptor) or lead to neuroendocrine differentiation (repression of the AR signaling pathway, TP53 mutations, and amplification of the AURKA or MYCN oncogene). Multistep therapy based on the data about somatic mutations associated with progression and metastasis of the primary tumor can be expected to significantly improve the survival of patients with advanced PCa in the nearest future.
恶性肿瘤的进展很大程度上归因于原发性肿瘤的克隆进化，即克隆获得不同的分子遗传损伤组合。这些损伤可赋予肿瘤细胞群体在增殖率或转移方面的选择性优势，尤其是在产生抗癌治疗耐药性时。前列腺癌（PCa）就是临床上显著克隆进化的一个典型例子。本综述探讨了原发性前列腺癌中发生的基因改变，以及激素难治性前列腺癌在激素治疗过程中发展的机制，包括雄激素受体基因（AR）的突变和可变剪接以及肿瘤内雄激素合成。某些分子遗传损伤决定了对新一代抑制剂的耐药性（阻止拮抗剂作用或允许其他激素激活受体的AR突变），或导致神经内分泌分化（AR信号通路的抑制、TP53突变以及AURKA或MYCN癌基因的扩增）。基于与原发性肿瘤进展和转移相关的体细胞突变数据的多步骤治疗有望在不久的将来显著提高晚期前列腺癌患者的生存率。
