修回日期: 2004-04-19
接受日期: 2004-04-29
在线出版日期: 2004-06-15
人类错配修复系统可以识别并纠正DNA复制过程中出现的错误. 错配修复系统缺陷使这些错误往往无法消除, 导致恶性肿瘤的发生. 患者经常表现出微卫星不稳定性. 目前发现与人类恶性肿瘤发病有关的错配修复基因包括hMSH2、hMSH3、hMSH6、hMLH1及hMLH3. 这些基因的突变在遗传性非息肉病性结直肠癌中的作用已得到广泛证实. 临床上很大一部分胃癌患者表现出微卫星不稳定性, 提示错配修复缺陷在胃癌的发病中亦起到重要作用. 众多的研究发现错配修复基因的突变在胃癌中并不常见, 而由于hMLH1启动子甲基化及失活所引起的错配修复缺陷成为胃癌发病机制中一条重要途径. 这些患者常具有微卫星不稳定性及独特的临床特征.
引文著录: 赵成海. 微卫星不稳定与胃癌. 世界华人消化杂志 2004; 12(6): 1384-1388
Revised: April 19, 2004
Accepted: April 29, 2004
Published online: June 15, 2004
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12(6): 1384-1388
- URL: https://www.wjgnet.com/1009-3079/full/v12/i6/1384.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v12.i6.1384
近10年来, 错配修复基因缺陷及由此导致的微卫星不稳定与肿瘤的关系, 特别是其在遗传性非息肉病性结直肠癌(HNPCC)中的作用, 临床上进行了广泛的研究. 同时许多研究显示, 错配修复系统缺陷在胃癌发病中也起到了一定作用, 现就这方面的相关研究做一简要综述.
DNA复制发生在细胞进行有丝分裂的准备期间. 由于发生复制错误再所难免, 因此机体进化出一些特异的修复系统以避免基因组中这些有害突变大量积聚. DNA错配修复系统作为一个重要的"基因看管者"(caretaker gene)[1]能够识别并及时纠正错配的DNA碱基对, 确保复制过程的保真性(fidelity). 一般而言, DNA复制错误主要发生在链伸长阶段, 最常见的错误为在DNA聚合酶作用下单一的碱基不正确地配对. 这样的错配几率大约每103-104碱基对发生一次. 由于修复机制的存在, 实际发生错误的几率远远低于这一数值. DNA复制过程中还可能出现另外一种错误. 由于DNA聚合酶复合物在复制微卫星DNA序列发生滑脱(slippage), 因此导致子链上这些微卫星序列长度延长或缩短. 在错配修复系统出现缺陷的情况下, 这些错误可能无法得到纠正, 这种现象即被称为微卫星不稳定(MSI). 不过需要指出, DNA聚合酶复合物本身也具有防止出现复制错误的功能. 该复合体中一种内源性酶的亚单位具有核酸外切酶的活性, 他能够及时发现错配的碱基对并将其切除. 同时在DNA聚合酶作用下合成正确的核苷酸. 但其机制目前仍不是十分清楚.
目前已发现的人类错配修复基因包括来自MutS家族的hMSH2、hMSH3和hMSH6及来自MutL家族的hMLH1、hPMS1、hPMS2和最新被鉴定出来的hMLH3. DNA错配修复机制需要这些基因互相合作完成. 简单而言, hMSH2能够识别错配的DNA序列并直接与其结合[2]. 如果是单个碱基错配, 他将和hMSH6形成异二聚体. 而如果是2-8个碱基丢失或插入, 他将和hMSH3形成异二聚体. 但有研究显示, 在hMSH6缺失的情况下, hMSH2/hMSH3也可以替代hMSH2/ hMSH6发挥作用. 显然在这一过程中hMSH2是必需的, 而hMSH6和hMSH3则表现出功能剩余[3]. 此后hMLH1和hPMS2形成另外一个异二聚体复合物与相关的DNA聚合酶配合将错配的碱基切除并修复. 另外hMLH1和hPMS1及hMLH1和 hMLH3均能形成异二聚体, 但其机制目前仍不清楚.
hMLH3是2000年克隆并定性的一种错配修复基因, 定位于14q24.3, 编码全区长4.3 kb, 由12个外显子组成[4]. 由于其存在与hMLH 1相互作用的区域, 且与酵母的MLH3极为相似[4], 因而可能替代hPMS2与hMLH 1形成复合物, 是另一个与人类恶性肿瘤有关的错配修复备选基因. 如同hMSH3和hMSH6, hMLH 3和hPMS2可能也具有类似的功能剩余. 目前临床上对hMLH 3的研究并不多, 关于其在肿瘤发病中的作用仍有待于进一步的探讨.
如前文所述, 错配修复缺陷将使由于DNA聚合酶复合物"滑脱"而引起的DNA序列微卫星长度变化无法得到修复, 导致微卫星及整个基因组的不稳定. 因此以错配修复缺陷为特征的肿瘤常常显示出微卫星不稳定这一表型改变. 1997年, 国际统一确定5个标准位点(marker)来鉴定MSI[5], 规定有两个或两个以上位点不稳定为高微卫星不稳定(MSI-H), 而只有一个位点和没有位点不稳定分别为MSI-L和MSS. MSI-H型肿瘤常常与另外两种类型的肿瘤具有不同的临床病理表现. 由于错配修复基因的单纯失活被认为无法直接引起细胞恶变, 因此在此过程中需要有其他基因参与. 目前发现这些基因中的大多数都含有编码重复序列, 这些编码重复序列在MSI-H肿瘤中特别容易出现改变, 故他们也被称为MSI-H肿瘤的靶基因. 第一个被报道的靶基因为TGFb-RⅡ[6], 在MSI-H结直肠癌中发现其移码突变. 且在随后的功能研究中发现, 这种移码突变导致了TGFb-RⅡ肿瘤抑制功能的丧失. 接下来众多的靶基因不断的被报道出来, 其中最为广泛的为BAX, hMSH3, hMSH6和IGFⅡR[7-9].
目前广泛认为肿瘤的发生是一个复杂生物学过程, 其中有众多基因的参与. 这些基因分别调节细胞生长及死亡, 细胞外基质重塑, 基因组的稳定性及DNA修复. 错配修复基因的缺陷将使DNA复制过程中出现的错误无法及时纠正, 使得基因突变事件不断放大积累, 使大量错误信息遍布整个基因组, 最终导致肿瘤的发生. 具体而言, 错配修复基因缺陷可能通过以下几个途径促进肿瘤的发生: (1)增加癌基因和抑癌基因的突变频率. (2)使另外一些重要的基因发生遗传的不稳定性. (3)通过一些化学物质对细胞的损伤导致肿瘤发生.
目前已发现错配修复缺陷与人类多个部位的肿瘤发生有关[10-12], 其中与HNPCC关系的研究最为广泛[13-15]. 90%以上的HNPCC家系可以检测到hMLH1和hMSH2的生殖系突变(http//http://www.nfdht.nl). hMSH6的生殖系突变在部分家系中起作用[16]. 而支持hPMS1和hPMS2在HNPCC起作用的证据则比较少[17]. 另外部分学者已在HNPCC家系中检测到hMLH3的移码突变和错义突变[18-19]. 但对hMLH3突变在HNPCC中的作用仍处于探索阶段.
由于HNPCC患者广泛存在hMLH1和hMSH2的生殖系突变, 因此家族性胃癌中是否存在这种突变引起了许多学者的兴趣. 然而迄今为止却鲜有证据支持这一设想. Keller et al[20]在家族性胃癌研究中对10例MSI阳性患者进行鉴定, 结果仅发现1例hMLH1生殖系错义突变. Yanagisawa et al[21]在对家族性胃癌患者检测中未发现hMLH1和hMSH2生殖系突变的存在. 另外Semba et al[22]及Bevilacqua et al[23]在对散发性胃癌的研究中亦未发现生殖系突变. 但部分研究人员检测出一些hMLH1或hMSH2的体细胞突变, 如Wu et al[24]在对12例MSI阳性胃癌患者检测中发现1例hMSH2错义突变. Semba et al[22]在年轻胃癌研究中发现3例体细胞突变. Fang et al[25]在68例胃癌患者中亦发现3例体细胞突变. 综上所述, 由于hMLH1和hMSH2突变在胃癌患者中出现的频率较低, 说明其在胃癌的发病机制中并不象在HNPCC那样占有重要地位.
hMSH3和hMSH6突变在HNPCC中较为常见. 由于他们本身含有单核苷酸重复序列, 因此他们同时也是MSI的靶基因. 即如同其他基因一样, 他们也可能由于其他的错配修复缺陷而出现变异. 有许多学者检测到hMSH6和/或hMSH3突变[26-30]. Menoyo et al[30]在研究中检测到的hMSH6和hMSH3移码突变更是高达43%和56%. 尽管有的学者在研究中未检测到hMSH6或hMLH3突变的存在[31], 但作为MSI的靶基因, 在MSI阳性的胃癌患者中, hMSH6及 hMSH3的突变仍然是一种较为常见的现象. hMLH3作为一种新近被定性的错配修复基因, 目前的相关的报道并不多. 其在HNPCC中的作用目前仍存在较多的争议. 其在胃癌发病中是否起作用更是不得而知. 目前仅有Menoyo et al[30]在胃癌患者中对其进行了研究. 结果没有发现移码突变的存在. 由于在HNPCC中研究人员发现的更多的是错义突变[18-19], 因此胃癌中是否存在hMLH3的错义突变有待于更多的研究.
尽管错配修复基因突变在胃癌中并不是一种常见的现象, 其在胃癌的发病机制中也不起重要作用. 但由于相当一部分胃癌患者存在MSI, 显示出错配修复缺陷仍是胃癌发病机制中一个重要途径. 1999年Leung et al[32]在对35例胃癌患者中的11例MSI-H分析中发现10例存在hMLH1启动子甲基化, 同时发现hMLH1表达消失. 结果显示MSI-H与hMLH1启动子甲基化及其表达失活具有相关性, 也提示hMLH1启动子甲基化导致该基因表遗传性(epigenetic)改变, 即基因失活及表达改变, 在部分胃癌的发病中可能起到一定作用. 此后又有众多学者[21,23,25,29,33-36]发现胃癌患者中存在hMLH1启动子甲基化及其表达改变. 大多数研究显示MSI-H与hMLH1启动子甲基化相关, 而MSI-L和MSS患者几乎不存在这种情况. 这一情况显示hMLH1启动子甲基化可导致MSI-H. 然而hMLH1启动子甲基化胃癌并不肯定出现MSI, 而MSI-H胃癌患者也并不是全部存在hMLH1启动子甲基化[29,32]. Kang et al[37]研究发现hMLH1启动子只有特定的位置发生甲基化, 才能导致其表达的改变. 而最近的一项研究[38]进一步证实启动子近端的甲基化与MSI相关. 另外有一些研究发现其他一些基因的甲基化也似乎参与了胃癌的发病过程. Bae et al[39]及Tsujimoto et al[40]分别发现MGMT和P14ARF甲基化与MSI相关. Chan et al[41]研究发现hMLH1启动子甲基化与ID4甲基化具有相关性. Carvalho et al[36]在MSI-H胃癌中发现hMLH1与CDH1、MGMT及COχ2存在同时甲基化现象. 其各自的甲基化发生频率更是高达37%、51%、61%及29%. Kang et al[42]发现胃癌患者中hMLH1等10种基因存在甲基化情况, 其中hMLH1启动子甲基化频率为20%. 以上的这些研究显示, hMLH1启动子只有特定位置发生甲基化才能导致其表达改变及MSI. 同时其他基因的甲基化或其他基因与hMLH1同时的甲基化也参与了胃癌的发病过程.
由于部分胃癌患者存在hMLH1启动子甲基化及其表达消失, 一些学者也对hMSH2的表达情况进行了检测. Leung et al[32]在对MSI-H胃癌患者研究中发现hMLH1表达消失, 而hMSH2的表达却正常. Halling et al[33]在MSI胃癌中却观察到hMSH2表达消失. Zhang et al[43]发现hMSH2mRNA表达减少. Grogg et al[44]在对17例MSI检测中却发现hMSH2均正常表达.鉴于这方面的研究报道并不多, 显然无法就其得出一个明确的结论. 由于hMSH2并不象hMLH1那样存在甲基化而失活, 同时其发生突变的频率也很低, 故其表达消失的机制仍有待于进一步探讨. 总之, 在错配修复缺陷所致胃癌中, 错配修复基因突变似乎并不起主要作用, 更多的是由于hMLH1甲基化而致表达改变所引起. 作为MSI的靶基因, hMSH6和hMSH3的突变在MSI阳性的胃癌中较为常见. hMLH3在胃癌中所起的作用, 有待于进一步探讨.
散发性胃癌MSI阳性率大约在10-48%之间. 不同的研究结果存在较大差异跟以下几个因素有关: 首先位点选择存在明显的差异. 尽管1997年国际统一规定了检测MSI的5个标准位点, 但实际许多研究中采用的位点往往超过5个. 多数研究的位点在5-12个之间[20,24,28,45-53], Wang et al[54]在研究中采用位点高达29个, 其所检测出的MSI阳性率也达到34.1%. 由于位点选择的数量不同, 导致在MSI-H的定义上也存在明显的差异. 多数研究规定超过检测位点总数30%的位点出现变异即为MSI-H.在众多候选位点中, BAT-26被认为比其他位点更具有敏感性[55-56], 即大多数MSI阳性胃癌存在BAT-26变异. 其次胃癌样本差异较大. 样本的差异一方面体现在数量上, 较小的样本得出的结果往往不够准确. 另一方面, 样本的组成也存在很大的差异. 不同组织类型或不同发展时期的胃癌MSI的阳性率往往不同. 此外有研究显示不同地区胃癌患者中MSI阳性率也存在差异. Hayden et al[52]发现胃癌低发区英国胃癌MSI阳性率明显低于同处欧洲胃癌相对高发的葡萄牙. Sepulveda et al[50]在对照研究中发现韩国胃癌MSI阳性率明显高于美国及哥伦比亚等地区. Chetty et al[57]在对胃癌低发区南非患者检测中未发现有MSI-H存在, 显示南非也是MSI阳性率较低的地区. 以上这几项研究显示胃癌高发区中胃癌患者中存在较高的MSI阳性率.
胃癌中MSI的靶基因包括TGFb-RⅡ、BAX, hMSH3, hMSH6和IGFⅡ等. 其中最常见为TGFb-RⅡ[26,28-29,45,48,53,58-62]. 这些靶基因均含有单核苷酸重复序列. 在MSI阳性特别是MSI-H胃癌中常常出现这些序列的改变.
MSI阳性特别是MSI-H胃癌与其他胃癌相比具有明显不同的临床特征. 许多研究显示组织类型为肠型的胃癌更易出现MSI[29,43-44,46,48,60,63-65]. Fang et al[51]及Leung et al[66]发现肠化生组织中MSI阳性率亦高于周围组织. 同时有研究显示MSI阳性与分化程度正相关[43,64,67]. 在胃癌发展的各个时期, 多数研究显示MSI与进展期具有相关性[24,46,48,51,68]. 另外MSI-H还与胃窦部发病[33,46,48-67]、低淋巴结转移[29,48]、家族史[20-21,46,49]、高淋巴细胞浸润[33-44]、晚发[44,69]具有相关性. Wu et al[48]发现MSI与幽门螺旋菌感染具有相关性, Kim et al[70]在实验中发现螺旋菌可影响错配修复系统的稳定性.
MSI与预后之间是否具有关联目前仍存在较多争议. 一些研究发现MSI阳性胃癌患者预后要明显好于MSI阴性患者[29,71]. 但另外一些研究则未发现二者之间具有相关性[46,48]. Suzuki et al[72]在最近的研究中发现患者预后与MSI没有相关性, 而与整个基因组损害比例相关. Bataille et al[68]及Ott et al[73]对MSI阳性与胃癌化疗预后进行研究, 也发现二者之间不存在相关性. 总之, 错配修复基因的突变在胃癌中并不是一种常见的现象, 而多数具有微卫星不稳定的胃癌患者存在hMLH1启动子甲基化及失活. 因而由hMLH1甲基化所引起的错配修复缺陷成为胃癌发病机制中一条重要途径. 这些患者常具有微卫星不稳定性及独特的临床特征.
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