Recurrent rearrangements in prostate cancer: causes and therapeutic potential.
Recurrent rearrangements in prostate cancer: causes and therapeutic potential.
复制标题
DOI：
10.2174/1389450111314040006
复制
发表时间：
2013-04
影响因子：
3.2
通讯作者：
Maher CA
中科院分区：
文献类型：
--
作者：
White NM;Feng FY;Maher CA
DNA损伤和基因重排是癌症的标志。然而，基因融合作为癌症中的驱动突变一直是白血病和其他罕见情况的典型区别，直到最近发现基因融合事件发生在50%至75%的前列腺癌患者中。TMPRSS 2-ERG融合的发现引发了大量的发现和创新，导致通过基因融合事件的分子特征描绘前列腺癌。高通量测序数据的共同性增加，加上改进的生物信息学方法，不仅阐明了前列腺癌进展的分子基础，而且阐明了基因融合生物发生的机制。有趣的是，雄激素受体（AR），已经知道在前列腺癌肿瘤发生中发挥重要作用，最近被牵连在导致基因融合的过程中，通过诱导参与重排的基因的空间接近，促进双链DNA断裂（DSB）的形成，并促进非同源末端连接（NHEJ）的蛋白质的募集。我们对诱导基因组不稳定性的机制的理解的增加可能会导致改进的诊断和治疗策略。迄今为止，大多数前列腺癌患者可以根据其基因融合状态进行分子分层，从而增加定制更特异和有效治疗的可能性。
DNA damage and genetic rearrangements are hallmarks of cancer. However, gene fusions as driver mutations in cancer have classically been a distinction in leukemia and other rare instances until recently with the discovery of gene fusion events occurring in 50 to 75% of prostate cancer patients. The discovery of the TMPRSS2-ERG fusion sparked an onslaught of discovery and innovation resulting in a delineation of prostate cancer via a molecular signature of gene fusion events. The increased commonality of high-throughput sequencing data coupled with improved bioinformatics approaches not only elucidated the molecular underpinnings of prostate cancer progression, but the mechanisms of gene fusion biogenesis. Interestingly, the androgen receptor (AR), already known to play a significant role in prostate cancer tumorigenesis, has recently been implicated in the processes resulting in gene fusions by inducing the spatial proximity of genes involved in rearrangements, promoting the formation of double-strand DNA breaks (DSB), and facilitating the recruitment of proteins for non-homologous end-joining (NHEJ). Our increased understanding of the mechanisms inducing genomic instability may lead to improved diagnostic and therapeutic strategies. To date, the majority of prostate cancer patients can be molecularly stratified based on their gene fusion status thereby increasing the potential for tailoring more specific and effective therapies.