在臨床上，治療前列腺癌的首選方法是抑制體內(nèi)雄激素水平,。但在經(jīng)過(guò)一段時(shí)間的激素治療,，病情經(jīng)歷一個(gè)停滯期后，多數(shù)患者對(duì)于激素治療開(kāi)始變得不敏感,，轉(zhuǎn)變?yōu)樾奂に氐挚剐缘那傲邢侔?castration-resistant prostate cancer,CRPC),，目前臨床上對(duì)于這種情況仍沒(méi)有有效的治療措施。
通過(guò)對(duì)前列腺癌轉(zhuǎn)錄組和基因組特征的研究發(fā)現(xiàn),，在前列腺癌細(xì)胞中,，存在著染色體重排，基因拷貝數(shù)增加或減少等異?，F(xiàn)象,。包括ETS家族基因融合、PTEN缺失和雄激素受體（androgen receptor, AR）擴(kuò)增等,。這些染色體異常會(huì)促進(jìn)前列腺癌的發(fā)展,，并最終形成致死的雄激素抵抗性前列腺癌,。但是基因突變?cè)谇傲邢侔┑陌l(fā)展中扮演著怎樣的角色,，目前我們還知之甚少。
本文中,，作者對(duì)50個(gè)接受過(guò)重度激素治療的轉(zhuǎn)移性CRPC樣本（其中有3個(gè)是來(lái)自同一患者的不同病變組織）和11個(gè)輕度激素治療的局部前列腺癌樣本進(jìn)行外顯子組測(cè)序比較,。研究者找到了致死性CRPC的單克隆起源，并發(fā)現(xiàn)即使在重度激素治療的CRPC中,，突變的頻率也是很低的,。外顯子拷貝數(shù)分析顯示，在一類前列腺癌細(xì)胞中存在著CHD1的缺失,，研究者據(jù)此定義了一個(gè)新的EST-前列腺癌亞型,。而EST2在前列腺癌細(xì)胞中的異常表現(xiàn)為融合缺失和突變兩種情況。此外,，研究者還鑒定了在多條染色質(zhì)上出現(xiàn)的頻發(fā)突變和組蛋白修飾基因,，其中包括編碼H3K4甲基轉(zhuǎn)移酶的特異基因MLL2（在8.6%的前列腺癌中發(fā)生突變）。MLL2復(fù)合體能夠與AR相互作用,，這種作用在AR介導(dǎo)的信號(hào)通路中是必需的,。同時(shí)，研究者也檢測(cè)了FOXA1的異常頻發(fā)突變,，F(xiàn)OXA1是能與AR協(xié)同作用的因子,，在147個(gè)樣本中，有5個(gè)樣本的FOXA1發(fā)生了突變。FOXA1的突變會(huì)抑制雄激素途徑,，并促進(jìn)腫瘤的生長(zhǎng),。在一些與AR直接相互作用的蛋白，比如ERG基因融合產(chǎn)物,、FOXA1,、MLL2、UTX和ASXL1中均檢測(cè)到了突變,。
簡(jiǎn)而言之,，通過(guò)對(duì)于雄激素抵抗性前列腺癌的突變位點(diǎn)進(jìn)行分析，有助于了解AR信號(hào)通路在前列腺癌發(fā)展中是如何變得不受控制的,。同時(shí)該項(xiàng)研究的結(jié)果也能為前列腺癌的后續(xù)研究提供候選基因,。（生物谷 Bioon.com ）
doi:10.1038/nature11125
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The mutational landscape of lethal castration-resistant prostate cancer
Catherine S. Grasso, Yi-Mi Wu, Dan R. Robinson,Xuhong Cao, Saravana M. Dhanasekaran, Amjad P. Khan, Michael J. Quist, Xiaojun Jing, Robert J. Lonigro, J. Chad Brenner, Irfan A. Asangani, Bushra Ateeq, Sang Y. Chun, Javed Siddiqui, Lee Sam, Matt Anstett, Rohit Mehra, John R. Prensner, Nallasivam Palanisamy, Gregory A. Ryslik, Fabio Vandin, Benjamin J. Raphael, Lakshmi P. Kunju, Daniel R. Rhodes, Kenneth J. Pienta, Arul M. Chinnaiyan & Scott A. Tomlins et al. .
Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC)1. However, less is known about the role of mutations2, 3, 4. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.
