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. 2021 May 28;46(5):552–557. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2021.190427

基因组不稳定性与淋巴瘤

Genome instability and lymphoma

CAO Pengfei 1,2,2, LI Guiyuan 2,✉, XIANG Juanjuan 2
Editor: 郭 征
PMCID: PMC10930211  PMID: 34148893

Abstract

Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of lymphoma, but also has important value in the diagnosis and prognosis of lymphoma. There are 2 types of genome instability: Microsatellite instability (MSI/MIN) at gene level and chromosomal instability at chromosome level. Through the study on genes associated with lymphoma, the unstable genes associated with lymphoma could be found, meanwhile the mechanism of its occurrence and development of lymphoma could be explored, and the important basis of molecular biology could also be provided in the field of current hot lymphoma precision medical research.

Keywords: lymphoma, genome instability, microsatellite instability, chromosomal instability

维持基因组的完整性和忠实性是所有生物体生存繁衍、维持正常功能的基础[1-2]。当发生DNA突变或基因组不稳定性(genome instability，GI)时，细胞的转录及复制出现异常，细胞失去稳定性[3]。GI包括DNA自身的不稳定性及DNA受到内源性或外源性遗传毒性物质突然而猛烈的攻击后发生的核苷酸错掺[4]。如果GI得到累积，基因的遗传就会发生紊乱，导致细胞衰老加剧甚至癌变[5]。

人类大多数肿瘤都有GI的表现[6]。GI包括两种类型：基因水平的微卫星不稳定性(microsatellite instability，MSI/MIN)和染色体水平的染色体不稳定性(chromosomal instability，CIN)[7]。绝大多数肿瘤表现为CIN，细胞周期检查点紊乱、染色体分离、DNA损伤反应及端粒功能的缺陷或丧失等多种细胞功能障碍都可导致发生CIN。CIN是指癌细胞较之于正常细胞出现的染色体数目及结构异常[8]。正常细胞很少出现染色体的错分离现象，但大多数肿瘤细胞出现GI表型，导致错分离现象而出现异常染色体增多甚至非整倍体染色体[9]。非整倍体染色体的出现不仅会使癌基因增加、肿瘤抑制基因缺失，还可减缓细胞增殖及打破机体的新陈代谢稳态。因此非整倍体染色体使肿瘤细胞获得选择优势的倾向[10-11]。

淋巴瘤是发生于淋巴结或结外淋巴组织的免疫系统恶性肿瘤，过去临床上主要通过病理形态学及免疫组织化学将其分为霍奇金淋巴瘤及非霍奇金淋巴瘤2种类型。近年来，由于淋巴瘤分子生物学研究的突飞猛进，通过MSI扫描分析、全基因组微卫星分析、比较基因组杂交、染色体分子杂交、荧光原位杂交技术、脆性位点分析、单核苷酸多态性分析、全基因组表达谱分析等分子生物学手段已发现90%以上的淋巴瘤都有基因组方面的异常[12-14]。最常见的是相互易位，如伯基特淋巴瘤(Burkitt lymphoma，BL)常存在8q24的Myc与伙伴染色体上的免疫球蛋白重链基因(immunoglobulin heavy chain H，IgH)之间 t(8; 14)染色体易位。由相互易位引起的GI导致远端DNA片段转到免疫球蛋白的基因上，使癌基因表达失控，这些癌基因的过度表达使细胞生长失控。

1. 基因水平的MSI与淋巴瘤

1.1. 细胞周期检查点紊乱与淋巴瘤的发生

细胞周期检查点是调控机体有条不紊地进行细胞活动所必需的生物学行为。如果细胞周期检查点发生协调错误，基因组稳定性的平衡会被打破。在多种血液系统肿瘤中都存在细胞周期检查点紊乱[15]。Green等[16]通过对霍奇金淋巴瘤高分辨重复序列及转录组学的联合分析，得出此类淋巴瘤的程序性死亡-1(programmed death-1，PD-1)及程序性死亡-2(programmed death-2，PD-2)位于9p24.1的核心靶序列，此区域包含JK2基因，而JK2基因具有酪氨酸激酶活性，在多种血液系统肿瘤的细胞周期调节过程中发挥作用。这些基因拷贝数目发生改变或发生重排，均可影响细胞周期检查点，导致霍奇金淋巴瘤特征性Reed-Sternberg细胞上PD-1过表达[16-17]。

DNA损伤检查点的主要成员包括ATM和Rad3相关激酶(ATM and Rad3 related，ATR)。ATM是DNA双链断裂(double strand breaks，DSB)反应的主要调节因子，ATR虽然只是DSB反应的替补元件，却是紫外线损伤及DNA复制停滞的主要作用因子[18]。ATM基因缺失的小鼠易患T细胞淋巴瘤[19]。但Hathcock等[20]发现缺失ATM基因的小鼠易患伴M球蛋白增多的B细胞淋巴瘤，患病小鼠在18号染色体上出现1个4.48 Mb的重现性基因扩增区域，其中包含MALT1基因，与人类ABC型弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma，DLBCL)患者是直系同源的基因区域。ATM基因的缺失还可使T细胞受体α(T cell receptor α，TCRα)/d-IgH基因发生重排。目前的研究[21-22]结果表明这种重排会造成不同分化阶段的胸腺细胞发生断裂基因的异常修复。核基因重组激活基因2(recombination activating gene 2，RAG2)激活环路的损伤可使同一种T细胞在同一分化周期内出现TCRα及IgH基因双位点断裂，机体发生内部位点的基因重排[23]。RAG2基因的羧基端和ATM基因都可预防RAG基因通过调节三维构象及这两个基因上的核组织介导的基因位点发生断裂。限制潜在底物发生基因转换也是保护基因稳定性的重要机制。Gilad等[24]发现ATR基因与癌基因Ras协同作用会增加基因组的不稳定性，从而导致淋巴瘤等相关肿瘤发生。

1.1.1. G1检查点

从有丝分裂到DNA复制前的一段时期为G1期，又称合成前期，其主要意义在于为下阶段S期的DNA复制做好物质和能量的准备。G1检查点主要受P53的调控，而P53的激活又受到ATM和ATR的调节。在P53信号通路上，P21作为细胞周期激酶抑制剂[25]，通过抑制Cyclin E/Cdk2激酶活性完成对G1期的调控[26-27]。

1.1.2. S期检查点

S期检查点可监视细胞周期的进程，从而减少DNA合成时的受损率。目前，对S期检查点参与淋巴瘤发生的机制研究甚少。鼠双微体2(murine double minute 2，MDM2)可降解P53，进而诱发S期检查点反应，抑制DNA复制启始位点的退火，在转基因小鼠中可成功诱发淋巴瘤[28]。

1.1.3. G2检查点

G2检查点是重要的细胞周期检查点，主要决定哪些悬浮的染色体可优先进入染色体分离程序。G2检查点的活性依赖于细胞周期激酶Cdc2。用Toll样受体9(Toll-like receptor 9，TLR9)抑制滤泡外B细胞G2检查点的激活，调控G1/S期，可抑制B细胞的增殖，从而避免自身免疫性疾病及淋巴瘤的发生[29]。

1.2. DNA修复与淋巴瘤

DNA修复指对突变DNA或局部受损DNA进行多种修复[DNA的直接逆转修复、碱基切除修复(base excision repair，BER)、DNA的错配修复(mismatch repair，MMR)、核酸的切除修复(nucleotide excision repair，NER)及DSB损伤修复等]，使子代DNA在复制过程中保持遗传上的高保真性与忠实性。任何修复途径受损均与淋巴瘤的发生和发展相关。

1.2.1. DNA的直接逆转修复

直接逆转修复高度突变受损部位的DNA是人类DNA修复中最简单、有效的措施。一旦这种逆转机制受损，不能逆转的DNA可突变为肿瘤DNA，这也是淋巴瘤发生和发展的重要机制之一。DNA直接逆转修复途径受损与淋巴瘤发生和发展相关[30]。直接逆转修复突变的DNA可有效抑制B细胞非霍奇金淋巴瘤(B-cell non-Hodgkin’s lymphoma，B-NHL)细胞的凋亡[31]。

1.2.2. BER

BER是维持机体DNA保真性的重要修复机制，它是机体修复氧化、甲基化、乙酰化及自发突变的DNA的有效方式之一。在C57BL/6J转基因小鼠中发现BER受阻可诱导原发性胸腺淋巴瘤发生，提示BER与淋巴瘤的发生相关[32]。

1.2.3. DNA的MMR

DNA的MMR可校正复制时发生的碱基-碱基错配及由于模板链滑动导致的核苷酸小缺失或插入，确保DNA合成的准确无误。Couronné等[33]应用高分辨比较基因组杂交(high resolution-comparative genomic hybridization，HR-CGH)技术对70例DLBCL患者进行检测，结果仅发现2例患者(分别为MSH2-MSH6及PMS2同型杂合子缺失)存在MMR，因此认为，相对于骨髓瘤等其他血液系统恶性肿瘤，MMR仅存在于极少数的淋巴瘤患者中。其他研究[34-35]也提供了相似的证据。

1.2.4. NER

NER是DNA修复机制中最为灵活的损伤修复机制，可以在受损DNA局部直接切除突变DNA。Monroy等[36]通过研究200例霍奇金淋巴瘤患者的单核苷酸多态性(single nucleotide polymorphism，SNP)，发现XPC Ala499Val、NBN Glu185Gln、XRCC3 Thr241Me、XRCC1 Arg194Trp和XRCC1 399Gln是导致霍奇金淋巴瘤的重要突变位点，通过NER机制修复这些突变位点后患霍奇金淋巴瘤的概率会下降。

1.2.5. DSB损伤修复

DSB损伤修复可引起肿瘤细胞死亡，分为同源重组修复和非同源重组修复。哺乳动物细胞以非同源重组修复为主。抑制载脂蛋白B mRNA编辑酶催化多肽样蛋白3G(APOBEC3G)基因的活性可阻断DSB损伤修复途径，且这种DSB损伤修复受阻与淋巴瘤的发生有关[37]。

2. 染色体水平的CIN与淋巴瘤

2.1. 淋巴瘤的染色体数目异常

正常人体细胞为二倍体细胞，肿瘤细胞多数为非整倍体。非整倍体有两种情况：1)超二倍体和亚二倍体；2)高异倍体(hyperaneuploid)。国外的文献研究染色体数目与急性白血病关系的较多，而研究染色体数目与淋巴瘤关系的颇少。在52例各类B-NHL患者中发现38例存在克隆性染色体异常，其中6例存在亚二倍体，10例存在超二倍体现象，其余22例为假二倍体；同时发现在各种亚型中，DLBCL发生非整倍体染色体的概率最高，其次为套细胞淋巴瘤及边缘区淋巴瘤[38]。尚未见淋巴瘤中高异倍体现象的报道，淋巴瘤可能不同于其他实体肿瘤，不存在此类染色体异常。

2.2. 淋巴瘤的染色体结构异常

染色体结构异常包括易位、缺失、扩增、环状染色体及双着丝粒染色体。这些异常都与淋巴瘤的发生和发展密切相关。

2.2.1. 染色体易位

易位发生在1条染色体内时称为染色体内易位(intrachromosomal translocation)，发生在2条同源或非同源染色体之间时称为染色体间易位(interchromosomal translocation)。多种淋巴瘤可发生染色体内易位和染色体间易位。t(11; 14)(q13; q32)造成细胞周期素D1(cyclin D1，CCND1)及IgH的易位是诊断套细胞淋巴瘤的金标准[39]。且这种易位与Myc基因共同存在时往往提示更差的预后[40]。t(8;14)的易位往往会导致Myc及IgH基因的重排，这也是Burkitt’s淋巴瘤的主要特征之一[41]。而存在t(14; 18)(q32; q21)易位的滤泡性淋巴瘤患者更易发生原癌基因bcl-2的过表达，bcl-2基因的突变与此类患者转化为恶性程度更高的淋巴瘤高度相关，是影响预后的独立因素[42-43]。Bcl-6与IgH重排也是DLBCL的常见异常，且与DBLCL的疾病进程相关，这些重排的基因常常导致一种或多种原癌基因的过表达，最终导致淋巴瘤的发生[44]。

2.2.2. 染色体缺失

在39%的滤泡性淋巴瘤患者及41%的DLBCL患者中存在基因的缺失或嵌合性突变缺失[45]。而多种淋巴瘤中均存在p53基因或ATM基因缺失[46]，p53基因位于染色体17p13，ATM基因位于染色体11q23，他们是目前研究得最为全面的2种抑癌基因，存在p53基因及ATM基因缺失的淋巴瘤往往预后不良[47-48]。

2.2.3. 染色体扩增

间变性淋巴瘤激酶(anaplastic lymphoma kinase，ALK)是一种存在扩增、突变、易位及倒置等多种遗传变异的酪氨酸激酶受体，常在多种肿瘤中充当癌基因的角色，也是间变性大细胞淋巴瘤中最常见一种基因异常[49]。而在一些少见的伴复杂染色体异常的套细胞淋巴瘤中也存在IgH/CCND1的扩增[50]。

2.2.4. 其他染色体异常

其他染色体异常包括倒位、突变及环状染色体等。T细胞淋巴瘤最容易出现7，14号染色体的倒位或易位[51]。通过外显子组学及转录组学分析，发现在53.3%的血管免疫母细胞性T细胞淋巴瘤中存在RHOA突变(p.Gly17Val)，这也是其区别于B细胞淋巴瘤的显著特征[52]。

3. 双打击淋巴瘤及三打击淋巴瘤

在B细胞淋巴瘤中，染色体易位常作为生物学或诊断学标志。双打击淋巴瘤是指Myc/8q24基因出现断裂点，且bcl-2和/或bcl-6基因发生染色体易位，形态上介于DLBCL及B细淋巴瘤之间的一种特殊类型的淋巴瘤[53-54]。在正常情况下，Myc基因位于染色体8q24，主要功能是促进细胞增殖。当细胞受到各种理化因素或生物因素的影响时，Myc基因会与其他基因(如IgH基因)发生重排，形成t(8; 14)(q24; q32)， t(8; 22)和/或t(2; 8)的融合基因[55]。同时，bcl-2和/或bcl-6基因也与IgH基因发生易位融合，这样机体由于受到Myc基因断裂及bcl-2/IgH基因和/或bcl-6/IgH基因易位的双/三重打击导致GI明显增高[56]，这种双/三打击淋巴瘤临床表现为高度侵袭性，Ki-67高，肿瘤细胞增殖快，预后差，对治疗不敏感[57]。

4. 结 语

GI是淋巴瘤的早期事件[58-59]，一般先从单个的核苷酸变异也就是点突变，DNA损伤后修复不完整，然后到多个位点的多基因突变，再到大家所熟知的癌前病变，最后发展成恶性肿瘤。在此过程中，一系列的基因组异常演变要经过DNA损伤、DNA损伤后修复不全、多位点的DNA损伤、染色体水平不稳定性的出现，最后发展成大片段的染色体异常改变、整条染色体的增加或丢失甚至少二倍体或多倍体。因此有些淋巴瘤在最终确诊时出现相对于正常个体基因组完全不同的基因图谱改变，研究这些差异表达的基因或基因图谱将有助于淋巴瘤的早期诊断、预后分层、精准治疗及治疗后的微小残留病灶的跟踪监测[60]。

总之，淋巴瘤的发生和发展是一个多因素、多阶段、多步骤的复杂过程，对淋巴瘤的研究也早已进入分子生物学时代，但淋巴瘤作为临床上公认的最复杂的肿瘤类型，目前的研究还远未达到真正意义上的精准医学水平，因此对淋巴瘤的GI这一领域的研究仍然具有重大意义。

基金资助

湖南省自然科学基金(2019JJ40487)；湖南省中医药管理局课题(201797)。

This work was supported by the Natural Science Foundation of Hunan Provice (2019JJ40487) and the Hunan Provincial Scientific Research Project of Traditional Chinese Medicine (201798), China.

利益冲突声明

作者声称无任何利益冲突。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202105552.pdf

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