Asian Case Reports in Oncology
Vol. 08  No. 01 ( 2019 ), Article ID: 28563 , 6 pages
10.12677/ACRPO.2019.81001

Advances in the Study of Microsatellite Instability and Clinical and Prognosis of Gastric Cancer

Yingchen Shi, Hao Fu, Hong Zhao*

Department of Oncology, Affiliated Hospital of Yan’an University, Yan’an Shaanxi

Received: Dec. 29th, 2018; accepted: Jan. 15th, 2019; published: Jan. 22nd, 2019

ABSTRACT

Microsatellite instability is a kind of classification subtype in gastric cancer and its formation mechanism and molecular structure have unique characteristics. A growing number of studies have shown that microsatellite instability and its subtypes have relationship with genetic, epigenetic, clinical pathologic features and the prognosis in different adjuvant therapy. In this paper, we will review the concept, formation and detection methods of microsatellite instability, and the relationship about pathogenesis, clinical and pathological characteristics of gastric cancer.

Keywords:MSI, Gastric Cancer, Detective Method, Clinicopathological Features, Prognosis

微卫星不稳定(MSI)与胃癌临床及预后的 研究进展

史颖晨,符号,赵红*

延安大学附属医院肿瘤科,陕西 延安

收稿日期:2018年12月29日;录用日期:2019年1月15日;发布日期:2019年1月22日

摘 要

胃癌中微卫星不稳定亚型是胃癌分型的一大类,其形成机制和分子学构成都有着独特的特征,日益增多的研究表明微卫星不稳定型胃癌及其亚型不管是在基因方面,表观遗传学方面,临床病理特征以及其与不同辅助治疗之间的预后都存在密切的关系。本文就微卫星不稳定的概念,形成及检测方法,与胃癌有关的发病机制,临床和病理特征及与预后有关的研究做一简单综述。

关键词 :微卫星不稳定,胃癌,检测方法,临床病理特征,预后

Copyright © 2019 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

胃癌是一个必须引起重视的全球性癌症,2018年,全球胃癌新发病例1,033,701例,占全部新发肿瘤人数的5.7%,死亡人数782,685例,占全部肿瘤死亡人数的8.2%。为第五个最常诊断的癌症,癌症死亡的第三大原因 [1] ,胃癌严重威胁着人类的健康。

2. 微卫星(Microsatellites, MS)

是一组特定的短串联基因重复序列,在整个人类基因组中大量存在,长度从核苷酸重复1到60次(通常是10到60次)不等。这些DNA基序分散在基因组的编码和非编码区域,在人群中高度多态性,但在个体中却相对较为稳定 [2] ,微卫星序列在染色体结构的形成和重组中起至关重要作用,其表达和突变可进一步影响基因的复制与表达。

3. 错配修复基因(Mismatch repair, MMR)

错配修复基因经转录翻译后表达相应的错配修复蛋白,MMR在检测到复制错误(例如,碱基不匹配、插入和删除)时对其进行定位和纠正 [3] ,因此,MMR可以将DNA错误减少100到1000倍,并防止它们在细胞增殖过程中成为固定突变 [4] ,即可以消除新合成DNA的错误,提高DNA复制的保真度。目前发现MMR相关蛋白至少七种蛋白质(h-MLH1、h-MLH3、h-MSH2、h-MSH3、h-MSH6、h-PMS1和h-PMS2)组成,由于它们与大肠杆菌MMR基因的同源性而得名。这些蛋白之间可两两形成功能性异质二聚体,识别DNA复制过程中发生的碱基对错配和小核苷酸插入/缺失(1~4个碱基对),负责监督正确的DNA复制 [5] 。

微卫星不稳定性(Microsatellites instability, MSI)

微卫星不稳定性是发生在MMR受损肿瘤中的一种高变异表型,其特征是由于DNA聚合酶滑脱以及单核苷酸变体(SNVs)频率升高而导致微卫星重复序列的广泛长度多态性 [6] ,进而导致与癌症相关的基因突变,缺乏错配修复(dMMR)细胞突变率的增加 [7] ,当MMR系统出现缺陷时,会导致基因组中持续存在不匹配的突变,特别是在重复DNA(微卫星)区域,从而导致微卫星不稳定性(MSI)。也有文章表明MSI也可能由于表观遗传变化或影响MMR蛋白的microRNA通路改变而发生 [8] 。近年来越来越多的研究也证实了MSI在包括结肠癌、胃癌和卵巢癌等几种癌症发病机制中的重要性 [9] 。

4. MSI检测与分型

1) 免疫组织化学(Immunohistochemistry IHC)

免疫组织化学法是常用的检测MMR蛋白方法。通过免疫组化法检测与MMR相关基因编码的MMR蛋白判断微卫星状态,这些蛋白包括MLH1、MSH2、MSH6和PMS2,研究表明MMR蛋白的缺失与MSI呈正相关,即当上述四种蛋白中任一蛋白表达阴性时标本就可判定为MSI-H,蛋白均表达阳性时则为MSS/MSI-L [10] 。IHC的优势在于简单、实用,且花费少,同时有研究报道IHC法检测MSI与PCR法结果相似 [11] 。

2) 聚合酶链式反应(PCR)

由于目前研究的结果有限,胃癌中的MSI诊断缺乏统一的标准,因此须遵循1998年NCI提出的针对HNPCC的MSI诊断标准:以BAT-25、BAT-26、D2S123、D5S346、D17S250这5个MS位点来定义。当出现两个或两个以上阳性位点(≥30%)时,样本判定为高度微卫星不稳定性(MSI-H),出现一个阳性位点(<30%)时,样本判定为低频微卫星不稳定(MSI-L),无阳性位点时则为微卫星稳定(MSS),而当检测位点多于这5个位点时,高度微卫星不稳定性(MSI-H)为出现 ≥ 30%~40%位点阳性,低频微卫星不稳定(MSI-L)为<30%~40% [12] ,而MSI-L与MSS之间的区别并没有明显的意义。

3) 新进展:单一标志物的快速识别

有2018年最新研究中有文献分析显示:在Thomsen-Friedenreich (TF)抗原的表达与MSI状态之间存在极显著的关联(p < 0.001),并在此提出了胃癌MSI的首个单一标志物的鉴定,特异性94% (16/17),敏感性69.2% (9/13),阴性预测值80% (16/20),阳性预测值90% (9/10)。通过简单的抗体检测,可以检测出TF抗原,对于胃健康和癌前上皮未检测到的癌具有高度特异性。这一发现为新的研究奠定了基础,并有望在临床环境中改善MSI的快速识别 [13] 。

总体而言,目前因所选的MS位点的数量和类型不同,众多学者研究得出的结论也各有千秋,这也提示我们需要对胃癌的MSI诊断进行研究,进而尽快制定一个统一的诊断标准,以便于为胃癌患者制订更有预测性、个性化的治疗方案,使胃癌患者能得到更优的诊疗效果。

5. MSI与胃癌发病机制之间的关系

MSI产生的主要机制在胃癌与结直肠癌中有着很大的不同,结直肠癌中,h-MLH1和h-MSH2突变是MSI-H产生的主要原因,也有小部分是由于h-MSH6、h-PMS1和h-PMS2突变所致,然而在MSI-H胃癌中前两者的突变相对较少,分别为15%和12%,而因h-MLH1启动子甲基化导致肿瘤的发生数量超过50% [14] 。如Leung在1999年对35例胃癌患者中的11例MSI-H分析中发现,90%的病例存在h-MLHl启动子CpG岛的高甲基化进而导致的hMLH1蛋白完全丢失,hMLH1 mRNA水平明显下降。结果显示高度微卫星不稳定主要是由于hMLH1的表观遗传失活与启动子甲基化,在部分胃癌的发病中可能起到一定作用,而且hMLH1蛋白的缺失还是侵袭性肿瘤发生发展中的一个重要事件 [15] 。

6. MSI分型与胃癌不同临床病理特征的关系

近年来,许多出版物及荟萃分析从临床角度对MSI进行了描述,发现MSI占所有胃癌的5.6%至33.3%,与女性、高龄(65岁或者65岁上下) [16] 、Lauren分型肠型、胃中/下部、N0状态、TNM I/II期有很强的相关性,总体生存率较高 [17] [18] [19] ,较容易发生淋巴道转移。MSS亚型发生年龄(60岁上下)要低于其他亚型,多处于阶段III/IV且EB病毒的感染率更高。MSI-H亚型主要发生于胃窦(75%),>60%为肠型,>50%为早期诊断(I/II) [20] [21] 。

7. MSI不同分型与预后

由于目前属于关于胃癌研究的初级阶段,因此预后与化疗有关的研究大多关于结直肠癌,其研究结果可供参考。

大约从1998年开始,我们已经知道大多数MSI-H CRC患者与MSS CRC患者相比,形成了一个独特的亚群,其特点是具有差异性,较不具侵略性的临床行为和良好的预后 [22] [23] 。最近的大型试验 [24] [25] [26] ,meta分析 [27] ,以及一些早期报道的回顾性研究 [28] [29] ,均支持MSI-H相对于MSS CRC患者为良好分型。但当辅助治疗方式不同时,这一结论就不一定完全成立。

1) 和化疗有关的预后:

目前关于MSI与胃癌化疗预后之间的关系研究结果多与结肠癌相似,都存在较多的争议 [30] 。Oki认为,MSI状态与5-FU辅助化疗后的存活率无相关性,且与5-FU敏感性无相关性,进而得出MSI状态对胃癌患者5-FU辅助化疗的总体生存率和反应无明显影响 [31] 。但另外一些研究研究则认为5-FU辅助化疗对MSI型无益但对MSS型有着有利影响。

于此争议,Kim进行了更深一步的研究。作者回顾性研究了约1300例接受了胃肠切除术的II期和III期胃癌患者的病例资料。研究结果显示:在亚组分析中,MSI-H在III期、伴有淋巴结转移的女性和未接受化疗的未分化组织学亚组预后较好。然而,在接受化疗的患者中,MSI-H肿瘤在III期、未分化组织学、弥漫型胃癌亚群预后较差。得出MSI-H相对于MSI-L在未接受以化疗为主的辅助性治疗时生存期更长,但当两者都接受化疗时,两者之间的总体生存率之间则并没有明显的差异。由此可以看出,化疗其实削弱了MSI-H型胃癌预后好的益处,也就是说化疗因素作为混杂因子影响了MSI不同分型在胃癌中作为预后标志物的作用。因此,仅仅将MSI作为胃癌一个预后标志物而进行胃癌化疗给药可能不再是合理的,化疗对MSI-H胃癌预后的影响也应该作为一个因素参与到以后的研究以及治疗中 [32] 。

2) 和手术有关的预后:

有学者观察病例为两大欧洲中心型前瞻性数据库(Siena, Italy and Kiel, Germany)中均接受过手术,并在手术时被诊断为同步期胃癌(远处淋巴结、腹膜细胞学阳性、腹膜和远处转移)的患者资料和生存数据得出:当症状难以控制而必须对转移性胃癌进行手术治疗时,在手术切除时检测到MSI胃癌并转移性疾病的患者,与相同条件下MSS癌症患者相比生存率更高。虽然MSI和MSS患者的临床特征、病理特征和转移灶类型无明显差异。但MSI-H患者的OS优于MSS患者,且经手术治疗的MSI-H期胃癌患者比MSS期胃癌患者存活率更高。因而需要进一步分析手术在MSI型胃癌中的作用 [33] 。

8. 小结与展望

在对胃癌研究日益深入的今天,探究MSI型胃癌形成机制、分子特征及临床病理特征及预后等有助于实现疾病的更精准诊断,对病人的个体化治疗方案的制定也有着及其重要作用。然而目前的研究中我们仍缺少对于MSI胃癌亚组分型的明确统一标准,其与化疗等其他辅助治疗之间的联合治疗关系尚不能十分确定,使其不能拥有统一的预后影响因素标准。因此,这还需要我们的进一步努力研究,以获得更明确的研究成果,为胃癌的诊治增砖添瓦。

文章引用

史颖晨,符 号,赵 红. 微卫星不稳定(MSI)与胃癌临床及预后的研究进展
Advances in the Study of Microsatellite Instability and Clinical and Prognosis of Gastric Cancer[J]. 亚洲肿瘤科病例研究, 2019, 08(01): 1-6. https://doi.org/10.12677/ACRPO.2019.81001

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