修回日期: 2006-05-20
接受日期: 2006-05-26
在线出版日期: 2006-08-08
目的: 探讨人胃癌组织中癌基因c-myc, 抑癌基因p16INK4A, p21WAF1, 错配修复基因hMLH1和hMSH2的甲基化状态及其表达与叶酸、MTHFR基因多态性的关系.
方法: 胃癌38例手术切除标本的癌区、癌旁和外周正常黏膜组织, 运用FOL ACS: 180自动化学发光系统测定叶酸含量, PCR-RFLP技术检测MTHFR基因677 (C→T)和1298 (A→C)两个常见多态, 并分别以Real-time RT-PCR和甲基化特异性PCR (MSP)技术检测肿瘤相关基因的表达和甲基化状态.
结果: c-myc表达升高, p16INK4A, hMLH1和hMSH2表达降低的胃癌黏膜组织其基因启动子区异常甲基化. p21WAF1, hMSH2表达降低, p16INK4A高甲基化者叶酸水平明显降低, c-myc低甲基化和表达升高者中均存在低叶酸水平. MTHFR 677CC基因型的胃癌黏膜组织p16INK4A甲基化升高且表达降低, 而其余肿瘤相关基因的甲基化及其表达与MTHFR两个常见多态均无明显相关性.
结论: DNA甲基化在胃癌的发生、发展中具有重要作用, 叶酸水平和MTHFR基因多态性通过影响部分肿瘤相关基因的甲基化状态而调控其表达.
引文著录: 翁玉蓉, 房静远, 孙丹凤, 陈朝飞, 陆嵘, 顾伟齐, 朱红音. 胃癌组织中肿瘤相关基因甲基化及其表达与叶酸和代谢酶MTHFR基因多态性的关系. 世界华人消化杂志 2006; 14(22): 2192-2198
Revised: May 20, 2006
Accepted: May 26, 2006
Published online: August 8, 2006
AIM: To investigate the methylation and expression of c-myc oncogenes, p16INK4A, p21WAF1, hMLH1 and hMSH2 tumor suppressor genes, and their associations with folate and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in gastric cancerous tissues.
METHODS: Paired samples of primary gastric cancer and corresponding para-cancerous, non-cancerous gastric mucosa were obtained from surgically resected specimens of 38 patients, and the latter were used as controls. Folate concentration was detected by FOL ACS: 180 automated chemiluminescence system. Two common polymorphisms of MTHFR gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The mRNA expression of tumor-related gene was detected by real-time reverse transcription-PCR (RT-PCR). The methylation status of gene promoter was determined by methylation-specific PCR (MSP).
RESULTS: Up-regulation of c-myc, down-regulation of p16INK4A, hMLH1 and hMSH2 expression were associated with the aberrant methylation of gene promoters in gastric canceous mucosae, while p21WAF1 expression was not. Down-regulation of p21WAF1 and hMSH2 expression, hypermethylation of p16INK4A were associated with low folate level. Over-expression and hypomethylation of c-myc coexisted with low folate level. 677CC genotype of MTHFR showed hypermethylation and down-regulation of p16INK4A expression, and there was no significant relationship between the two common polymorphisms of MTHFR and the methylation and expression of the other tumor-related genes.
CONCLUSION: DNA methylation plays an important role in human gastric carcinogenesis. Folate level and MTHFR gene polymorphisms may regulate the expression of tumor-related genes by affecting the methylation status.
- Citation: Weng YR, Fang JY, Sun DF, Chen ZF, Lu R, Gu WQ, Zhu HY. Methylation and expression of tumor-related genes and their associations with folate and MTHFR gene polymorphisms in gastric cancerous tissues. Shijie Huaren Xiaohua Zazhi 2006; 14(22): 2192-2198
- URL: https://www.wjgnet.com/1009-3079/full/v14/i22/2192.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v14.i22.2192
DNA甲基化是表观遗传修饰的主要内容之一, 他通过影响癌基因和抑癌基因的表达以及基因组的稳定性而参与肿瘤的发生与发展. 叶酸是主要的甲基基团供体, 叶酸缺乏通过破坏总基因DNA低甲基化、DNA合成与修复失常而发挥致癌作用[1]. 亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase, MTHFR)是叶酸代谢途径的关键酶之一, 他有2个常见多态, 即677 (C→T)和1298 (A→C). 突变的基因型增加酶的热不稳定性并降低其活性, 从而影响DNA甲基化和核酸的稳定性[2-4]. 胃癌是消化系统最常见的恶性肿瘤, 其发生、发展与癌基因的过度表达和抑癌基因的失活等有关. 我们研究胃癌发生、发展过程中叶酸和代谢酶MTHFR基因多态性对癌基因c-myc, 抑癌基因p16INK4A, p21WAF1, 错配修复基因hMLH1和hMSH2的甲基化状态及其表达的影响.
2004-07/2005-01组织学确诊为胃癌的手术患者38例. 年龄31-91(平均61.7±14.7)岁, 其中≥60岁22例, <60岁16例. 男25例, 女13例. 肿瘤直径≥5 cm 20例, <5 cm 18例. 淋巴结转移20例, 无转移18例. TNM临床分期:Ⅰ期5例, Ⅱ期21例, Ⅲ期12例. 标本分为3部分, 癌区组织取自癌灶中央非坏死部分, 癌旁组织取自距癌灶边缘5 cm以内的黏膜组织, 外周正常组织取自距癌灶边缘5 cm以上的黏膜组织, 切除后立即置液氮冻存. 病例临床资料完整, 并且术前均未进行任何抗肿瘤治疗. 所有标本均经本院2位高年资病理科医生证实. 全部病理诊断基于HE染色和根据WHO组织学诊断标准. 癌旁组织的病理学特征为炎症, 部分伴有肠化和异型增生.
组织叶酸含量检测和MTHFR基因型检测见文献[5]. 肿瘤相关基因的表达运用Real-time RT-PCR技术. (1)分别提取不同来源组织RNA (Trizol, Gibco BRL); (2)逆转录50 μL体系中将10 μg RNA逆转录为cDNA; (3)Real-time PCR采用定量PCR中的相对定量法, 以β-actin作为内参照, 同时以外周正常组织为基准, 癌区和癌旁组织RNA的肿瘤相关基因(x)表达量均表达成外周正常组织的N倍即(Nx). 每次定量反应后产物都经30 g/L琼脂糖电泳证明为所需扩增的片段. 通常情况下, 正常组织此值将位于0.3-3.0之间, Nx≥3为表达升高, 而≤0.3为表达降低[6]. 反应条件94℃ 5 min, 92℃ 15 s, 60℃ 1 min, 40个循环. 每次反应均作3复孔, CT取其均值. 引物和探针序列见表1. 肿瘤相关基因甲基化分析: (1)分别提取不同来源组织DNA (QlAamp DNA Mini Kit); (2)DNA亚硫酸氢盐处理(CpGenomeTM Universal DNA Modification Kit, Chemicon): DNA经过亚硫酸氢盐的化学修饰, 单链DNA中的所有的非甲基化的胞嘧啶都会发生脱氨基作用而转变成尿嘧啶, 而甲基化的胞嘧啶则不被修饰, 仍保持5-甲基胞嘧啶状态; (3)甲基化特异性PCR (MSP): 引物序列及PCR扩增条件见表2; (4)PCR产物采用20 g/L琼脂糖电泳, 生物电泳图像系统分析结果.
| 基因 | 正义引物(5'-3') | 反义引物(5'-3') | 探针 | 基因登录号 |
| β-actin | CTG GCA CCC AGC ACA ATG | GGA CAG CGA GGC CAG GAT | ATC ATT GCT CCT CCT GAG | BC016045 |
| p16INK4A | CAT AGA TGC CGC GGA AGG T | CAG AGC CTC TCT GGT TCT TTC AA | CCT CAG ACA TCC CCG | NM_058197 |
| p21WAF1 | CTG GAG ACT CTC AGG GTC GAA | GGA TTA GGG CTT CCT CTT GGA | ACG GCG GCA GAC CAG CAT GA | NM_078467 |
| c-myc | ACA CCG CCC ACC ACC AG | CCA CAG AAA CAA CAT CGA TTT CTT | AGC GAC TCT GAG GAG G | V00568 |
| hMLH1 | GGC CAG CTA ATG CTA TCA AAG AG | CTT TAA CAA TCA CTT GAA TAC TTG TGG A | ATT GAG AAC TGT TTA GAT GCA | U07418 |
| hMSH2 | ATC CAA GGA GAA TGA TTG GTA TTT G | CAA AGA GAA TGT CTT CAA ACT GAG AGA | CAT ATA AGG CTT CTC CTG GC | U04045 |
| 基因 | 正义引物(5'-3') | 反义引物(5'-3') | 反应条件 | 基因登录号 |
| p16INK4A (M) | TTA TTA GAG GGT | GAC CCC GAA CCG | 95℃ 5 min; 95℃ 30 s, 65℃ 30 s, | X94154 |
| GGG GCG GAT CGC | CGA CCG TAA | 72℃ 30 s, 40 cycles; 72℃ 5 min | ||
| p16INK4A (U) | GGG GGA GAT TTA | CCC TCC TCT TTC | 95℃ 5 min; 95℃ 30 s, 58℃ 30 s, | X94154 |
| ATT TGG | TTC CTC | 72℃ 30 s, 40 cycles; 72℃ 5 min | ||
| p21WAF1 (M) | TGT AGT ACG CGA | TCA ACT AAC GCA | 95℃ 5 min; 95℃ 40 s, 60℃ 40 s, | NM_007592 |
| GGT TTC G | ACT CAA CG | 72℃ 40 s, 40 cycles; 72℃ 5 min | ||
| p21WAF1 (U) | TTT TTG TAG TAT | AAC ACA ACT CAA | 95℃ 5 min; 95℃ 40 s, 56℃ 40 s, | NM_007592 |
| GTG AGG TTT TGG | CAC AAC CCT A | 72℃ 40 s, 40 cycles; 72℃ 5 min | ||
| c-myc (M) | TAG AAT TGG ATC | CGA CCG AAA ATC | 95℃ 5 min; 95℃ 1 min, 56℃ 2 min, | AF002859 |
| (exon1-2) | GGG GTA AA | AAC GCG AAT | 72℃ 3 min, 5 cycles; 95℃ 30 s, | |
| 56℃ 30 s, 72℃ 1 min, 35 cycles; | ||||
| 72℃ 5 min | ||||
| c-myc (U) | TAG AAT TGG ATT | CCA ACC AAA AAT | 95℃ 5 min; 95℃ 1 min, 56℃ 2 min, | AF002859 |
| (exon1-2) | GGG GTA AA | CAA CAT GAA T | 72℃ 3 min, 5 cycles; 95℃ 30 s, | |
| 56℃ 30 s, 72℃ 1 min, 35 cycles; | ||||
| 72℃ 5 min | ||||
| hMLH1 (M) | ACG TAG ACG TTT | CCT CAT CGT AAC | 95℃ 5 min; 95℃ 30 s, 60℃ 60 s, | AB017806 |
| TAT TAG GGT CGC | TAC CCG CG | 72℃ 60 s, 40 cycles; 72℃ 5 min | ||
| hMLH1 (U) | TTT TGA TGT AGA TGT | ACC ACC TCA TCA | 95℃ 5 min; 95℃ 30 s, 60℃ 60 s, | AB017806 |
| TTT ATT AGG GTT GT | TAA CTA CCC ACA | 72℃ 60 s, 40 cycles; 72℃ 5 min | ||
| hMSH2 (M) | TCG TGG TCG GAC | CAA CGT CTC CTT | 95℃ 5 min; 95℃ 30 s, 60℃ 60 s, | AB006445 |
| GTC GTT C | CGA CTA CAC CG | 72℃ 60 s, 40 cycles; 72℃ 5 min | ||
| hMSH2 (U) | GGT TGT TGT GGT | CAA CTA CAA CAT CTC | 95℃ 5 min; 95℃ 30 s, 60℃ 60 s, | AB006445 |
| TGG ATG TTG TTT | CTT CAA CTA CAC CA | 72℃ 60 s, 40 cycles; 72℃ 5 min |
Nx = 2-△△Ct
△△Ct = △Ct样品-△Ct基准 = (Ct样品x-Ct样品β-actin)-(Ct基准x-Ct基准β-actin)
统计学处理 采用SAS 6.12统计软件包进行统计处理. 通过方差分析进行均数间两两比较, 两样本率比较用确切概率计算法, P<0.05为差异有显著性.
与外周正常组织相比, 胃癌区组织中p21WAF1, hMLH1和hMSH2表达降低, c-myc表达升高(P<0.05), 而p16INK4A则无统计学显著差异(P>0.05); 胃癌旁组织中hMLH1表达降低, c-myc表达升高(P<0.05), 其余则无显著差异(P>0.05, 表3).
| 基因 | 组织 | 表达升高 | 无变化 | 表达降低 | Nx |
| p16INK4A | 癌旁 | 2(5.3) | 22(57.9) | 14(36.8) | 0.78±0.82 |
| 癌区 | 2(5.3) | 13(34.2) | 23(60.5) | 0.70±0.93 | |
| p21WAF1 | 癌旁 | 3(7.9) | 22(57.9) | 13(34.2) | 0.93±1.01 |
| 癌区 | 2(5.3) | 14(36.8) | 22(57.9) | 0.70±0.86a | |
| hMLH1 | 癌旁 | 1(2.6) | 20(52.6) | 17(44.7) | 0.66±0.92a |
| 癌区 | 2(5.3) | 14(36.8) | 22(57.9) | 0.61±0.86a | |
| hMSH2 | 癌旁 | 2(5.3) | 20(52.6) | 16(42.1) | 0.82±1.22 |
| 癌区 | 1(2.6) | 17(44.7) | 20(52.6) | 0.68±0.85a | |
| c-myc | 癌旁 | 14(36.8) | 21(55.3) | 3(7.9) | 2.76±3.44b |
| 癌区 | 19(50.0) | 15(39.5) | 4(10.5) | 3.27±2.88b |
p21WAF1和hMSH2表达降低的胃癌区组织叶酸含量明显低于表达升高者(图1), c-myc表达升高的胃癌区组织叶酸含量明显低于表达降低者(P<0.05), 而p16INK4A和hMLH1表达与叶酸含量无明显相关(P>0.05).
(1)677 (C→T)位点: hMSH2表达降低的胃癌区组织以CC基因型最多见, 其mRNA表达明显低于CT基因型, 与TT基因型相比有降低趋势; p21WAF1以CT基因型最多见, 与CC基因型相比有降低趋势; hMLH1则以CC基因型最多, 与TT基因型相比有降低趋势; 而p16INK4A以CC基因型最多, 与其余两种基因型相比无显著差异. c-myc表达升高的胃癌区组织以CT基因型最多见, 其mRNA表达明显高于CC基因型. (P<0.05) p16INK4A , c-myc甲基化紊乱以CC基因型多见, p21WAF1, hMLH1和hMSH2以CT基因型多见. (2)1298 (A→C)位点: c-myc表达升高的胃癌区组织以AA基因型最为多见, 其mRNA表达与AC基因型相比有降低趋势. 其余肿瘤相关基因表达降低者中3种基因型的mRNA表达无显著差异. 各基因甲基化紊乱均以AA基因型多见(表4, 图2).
| 基因 | MTHFR | 表达增强 | 无变化 | 表达减弱 | Nx |
| p16INK4A | 677CC | 1 | 3 | 10(71.4) | 0.63±1.05 |
| 677CT | 1 | 8 | 10(52.6) | 0.7±0.88 | |
| 677TT | 2 | 3(60.0) | 0.85±0.96 | ||
| 1298AA | 1 | 9 | 16(61.5) | 0.57±0.96 | |
| 1298AC | 1 | 4 | 7(58.3) | 0.81±1.15 | |
| p21WAF1 | 677CC | 1 | 7 | 6(42.9) | 1.06±1.06 |
| 677CT | 1 | 5 | 13(68.4) | 0.47±0.69 | |
| 677TT | 2 | 3(60.0) | 0.55±0.55 | ||
| 1298AA | 2 | 10 | 14(53.9) | 0.75±0.85 | |
| 1298AC | 4 | 8(66.7) | 0.58±0.85 | ||
| c-myc | 677CC | 6(42.9) | 7 | 1 | 2.26±2.17a |
| 677CT | 11(57.9) | 6 | 2 | 4.32±3.25 | |
| 677TT | 2(40.0) | 2 | 1 | 2.15±1.8 | |
| 1298AA | 15(57.9) | 8 | 3 | 3.84±3.17 | |
| 1298AC | 4(33.3) | 7 | 1 | 2.06±1.64 | |
| hMLH1 | 677CC | 3 | 11(78.6) | 0.46±0.67 | |
| 677CT | 1 | 8 | 10(52.6) | 0.57±0.82 | |
| 677TT | 1 | 3 | 1(25.0) | 1.3±1.28 | |
| 1298AA | 2 | 10 | 14(53.9) | 0.72±0.96 | |
| 1298AC | 4 | 8(66.8) | 0.39±0.55 | ||
| hMSH2 | 677CC | 5 | 9(64.3) | 0.31±0.32 | |
| 677CT | 1 | 10 | 8(42.1) | 0.88±0.97a | |
| 677TT | 3 | 2(40.0) | 0.94±1.12 | ||
| 1298AA | 1 | 13 | 12(46.2) | 0.8±0.98 | |
| 1298AC | 5 | 7(58.3) | 0.4±0.42 |
c-myc癌基因低甲基化见于表达升高者, 余基因中除有1例p21WAF1高甲基化见于表达无改变者, 高甲基化均见于表达降低者. 癌旁组p21WAF1有2例, p16INK4A和hMLH1各1例有高甲基化, 其余甲基化紊乱均见于癌区组, 外周正常组未有发现. 经统计学检验, 除p21WAF1外, 余基因的甲基化紊乱与其表达明显相关(P<0.05, 表5, 图3). p16INK4A高甲基化者叶酸水平明显低于非甲基化; c-myc低甲基化者叶酸水平与非甲基化相比有降低趋势; p21WAF1, hMLH1和hMSH2高甲基化者与非甲基化相比, 叶酸水平无统计学差异(表5).
胃癌是消化系统最常见的恶性肿瘤, 其发生、发展是一个多基因参加的多步骤过程, 包括癌基因的过度表达和抑癌基因的失活等[7]. DNA甲基化在基因表达调控中具有重要作用. 迄今为止, 已发现在大量的肿瘤细胞中抑癌基因失活与该基因启动子区过度甲基化有直接关系, 而过低甲基化则导致某些在正常情况下受到抑制的癌基因大量表达, 并可导致整个基因组的不稳定性增加. p16INK4A基因是一种抑癌基因, 对细胞周期起负调控作用. 在人胃癌中常可检测到p16IINK4A蛋白的缺失[8], 我们也发现胃癌区组织与外周正常组织相比p16INK4A mRNA表达有降低趋势(P = 0.054). 近来许多研究发现胃癌中p16INK4A基因的突变和纯合缺失并不多见, 该基因启动子区的甲基化紊乱是基因静默的主要机制[9-10]. 我们通过MSP方法检测发现p16INK4A mRNA低表达的癌区组织有9/23 (39.1%)存在DNA启动子区高甲基化, 而在p16INK4A表达升高或无变化的样品中却无1例存在此现象, 提示胃癌组织p16INK4A mRNA的表达降低与DNA甲基化有关.
p21WAF1基因上有p53作用的位点, 能Ð助p53发挥抑癌作用. 虽然信号传导、细胞分化或某些影响因子能改变p21WAF1 mRNA的稳定性, 但近来研究表明, p21WAF1启动子区高甲基化是该基因失活的可能机制[11-12]. 然而, Scott et al[13]发现, 5-aza-dC通过释放组蛋白脱乙酰化酶1(HDAC1)介导p21WAF1表达上调, 而该基因启动子区并未发生去甲基化. 我们发现, 胃癌区组织中p21WAF1表达明显低于外周正常组织, 其中表达降低者有7/22 (31.8%)、无变化者有1/16 (6.3%)存在高甲基化, 增高者中未发现甲基化紊乱现象(P>0.05). 提示胃癌组织中p21WAF1低表达, 但调控其表达的主要机制并非该基因的异常甲基化. 错配修复(mismatch repair, MMR)是细胞纠正复制错误的重要手段, 常出现在增殖过程中以维持基因的精确性, 对DNA复制的忠实性和基因组的稳定性起重要作用. MMR基因表达异常将会出现微卫星DNA的不稳定性或复制错误, 引起整个基因组不稳定性增加, 促使肿瘤发生[14-15]. hMLH1和hMSH2是MMR系统最为重要的2种基因成分. 现认为hMLH1基因启动子的继发性转录缺失与该基因启动子区的甲基化密切相关[16-17], 而对于DNA甲基化是否能引起hMSH2表达缺失仍有异议[18-19]. 本实验胃癌区组织中hMLH1和hMSH2表达水平明显低于外周正常组织, 其中表达降低的癌组织中高甲基化分别有8/22 (36.4%)和5/20 (25.0%), 而表达增强或无变化者中未发现异常甲基化. 这一结果说明hMLH1甲基化在胃癌的发生中起重要作用, 也提示DNA甲基化在一定程度上影响了hMSH2表达缺失[20].
c-myc是一个多功能的癌基因, 有转录因子活性, 可启动细胞增殖、抑制细胞分化、调节细胞周期并参与细胞凋亡的调控. 通常正常组织的c-myc基因3'端CCGG是被甲基化的, 只有少数细胞存在轻度低甲基化, 甲基化异常可导致该基因异常高表达, 进而参与肿瘤的发生、发展. 我们既往的研究显示, c-myc在胃癌[21]和肝癌[22]发生中甲基化水平降低. 本实验胃癌组织中c-myc过表达, 其mRNA表达水平明显高于外周正常组织, 其中6/19 (31.58%)的癌组织DNA启动子区低甲基化, 提示DNA低甲基化引起c-myc过度激活可能是胃癌发生的参与因素. 叶酸是主要的甲基基团供体, 他在调节包括细胞内甲基化反应和保持基因组稳定性方面具有重要作用, 其缺乏或代谢障碍与许多肿瘤的发病风险增高相关[23]. MTHFR不可逆催化5, 10-亚甲基四氢叶酸转变为5-甲基四氢叶酸, 他通过合成SAM而参与多种甲基化过程, 而酶活性的降低减少了同型半胱氨酸向甲硫氨酸的转变, 改变了SAM水平, 从而导致DNA低甲基化; 又通过胸腺嘧啶的合成参与DNA复制和细胞分化, 而其底物5, 10-亚甲基四氢叶酸减少, 使尿嘧啶错误掺入DNA, 被DNA修复系统识别和切除, 从而增加染色体的不稳定性[24]. 已有学者研究发现叶酸[25]和MTHFR基因多态性[26]与部分肿瘤相关基因甲基化紊乱有关, 但迄今缺乏针对胃癌的研究.
基于以上所述, 我们还研究了叶酸和MTHFR基因多态性与肿瘤相关基因甲基化及其表达的关系. 就叶酸而言, 胃癌黏膜中p21WAF1, hMSH2表达降低, p16INK4A高甲基化与低叶酸相关; 低叶酸通过使c-myc癌基因甲基化水平降低调控该基因表达. 就MTHFR基因2个多态位点而言, 胃癌区组织中携带677CC基因型的个体16INK4A甲基化升高而表达降低, 而其余肿瘤相关基因的甲基化及其表达与MTHFR 2个常见多态则无显著关系.
总之, 胃癌的发生是一个多基因、多阶段的复杂病变过程, 位点特异的DNA甲基化调控基因的表达, 癌基因的低甲基化和抑癌基因的高甲基化参与胃癌的发生、发展[27-28]. 叶酸缺乏及其代谢酶MTHFR多态性影响DNA的甲基化和核酸的稳定性, 从而参与肿瘤的形成. 由于样本数量有限, 我们未能探知实验设计中所有肿瘤相关基因与叶酸和MTHFR多态性的关系, 但从中可看出一定趋势, 即叶酸水平和MTHFR多态性通过影响部分肿瘤相关基因的甲基化状态而调控其表达. 大样本的实验有待开展, 以进一步验证我们的结果, 同时探讨各基因与胃癌组织分型及TMN分期的关系, 拓展对胃癌发病机制的研究
胃癌是消化系统最常见的恶性肿瘤, 其发生、发展与癌基因的过度表达和抑癌基因的失活等有关. 胃癌源于黏膜上皮细胞, 本文不以血液标本为研究对象, 而是以胃黏膜组织为研究对象, 平行观察了胃癌组织中多种肿瘤相关基因的甲基化状态及其表达与叶酸水平和代谢酶MTHFR基因多态性之间的关系.
文章平行观察了胃癌组织中多种癌相关基因的甲基化状态与叶酸水平及MTHFR之间关系, 发现叶酸水平和MTHFR基因多态性可以影响部分肿瘤相关基因的甲基化状态. 本研究内容较为前沿, 同时检测指标较多, 工作量较大, 研究结果具有一定指导意义.
电编:张敏 编辑:潘伯荣
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