7个鼻咽癌相关基因单核苷酸多态性的筛查及其与鼻咽癌易感性的关联分析
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摘要
中国人鼻咽癌(nasopharyngeal carcinoma，NPC)发病率居世界各民族之首，尤其高发于南方各省。流行病学调查结果表明NPC有显著的种族易感性和家族集聚现象，是一个多基因遗传病，涉及多种瘤基因、抑瘤基因的改变。病因学研究表明遗传因素、环境因素和EB病毒感染与NPC有关。国内外研究结果表明至今还没有发现公认的明确的鼻咽癌特异性致癌基因，但发现了一些与之密切相关的基因。
筛查和验证疾病相关基因的方法不少，而单核苷酸多态性(single nucleotide polymorphism，SNPs)作为第三代遗传标记因其分布密度高、遗传稳定性强和易实现分析的自动化的特性，被认为是目前人类遗传性和遗传相关性疾病的诊断以及群体遗传学的研究、药物的开发和应用等方面最佳检测方法。
本实验采用生物信息学方法搜寻筛查在遗传易感、病毒感染和化学促(致)癌等方面与鼻咽癌发病有密切关系的、具有代表性的7个基因进行SNP研究，其中YH1、NAG22、NPCR是鼻咽癌相关的抑瘤基因的侯选基因，CR2是介导EBV进入淋巴细胞的受体，TSG101是肿瘤抑制基因，同时也是体内广泛分布的一种多脏器代谢酶，CYP2E1及GSTml是体内重要的Ⅰ相代谢酶和Ⅱ相代谢酶的代表。这些基因与鼻咽癌发病机理有不同程度的关联，可以促使我们从不同角度来探讨和加深对鼻咽癌发病机理的认识。
用测序的方法从中华民族27个个体和5个pool中共筛查出具有中华民族特征的SNP102个，其中5′Flank46个，5′UTR9个，Coding14个，Intron18个，3′UTR11个，3′Flank14个。在102个多态位点中，有73
个为首次发现。14个csNP中7个为中高频位点(罕见等位基因频率为
7.40%一32.7%)，其中2个位点无氨基酸改变;余5个为低频位点(罕见
等位基因频率为1.9%)，其中1个位点无氨基酸改变。
对102个SNP多态位点中频率大于0.01、其它数据完整的87个SNP
进行连锁不平衡分析，结果表明有83对位点之间呈高度连锁不平衡尤况2
l对;11了121对;刀且G221对;TSGI019对;刃尸C尺29对;GS乃nl 13
对:CYPZEllZ对。
采用病例一对照的方法在238例鼻咽癌患者和286例正常对照人群
中，用RFLP一PCR、tetra一Pri~ARMS一PCR和测序分型方法对6个基因
(K片了、C尺2、刀摊G22、N尸C尺、TSGIOI和G 57初I)eSNP12个位点、YHI
基因调控区2个SNP位点以及通过单倍型计算获得的CYPZE13个htSNP
位点展开基因分型，用OR值来评估这些基因的基因型与鼻咽癌表型之
间的相对危险度，发现:
用K日了、CRZ、入摊G22、刃尸C尺低频SNP位点(延1 .9%)进行群体
分型实际意义不大，更不能以此单独作为某一种界标。
Gs乃nl C1270533T为首次发现的多态位点(中国人群罕见等位基因
rl，频率为22.2%)，其96位氨基酸的第二位密码子发生了碱基颠换(CGT
一C竹)，使沁g一Leu，导致错义突变。分型结果表明，基因型TT和
GT的RR值分别为0.170和0.605，该位点的表型与鼻咽癌无关联。
KHZ调控区2个SNP位点(中国人群罕见等位基因频率分别为37.0%
和38.9%)，K“2 G199O158A基因型GG携带者患鼻咽癌的危险性是对照
人群的2.3倍(95%置信区间为1.458一3.628);K阿2 G1990398T基因型
GG携带者发生鼻咽癌的可能性是对照人群的3.166倍(95%置信区间为
1 .784一5.619)。
CYPZEI cSNp位点T505228A，其421位氨基酸的第三位密码子发
生了碱基颠换(TTC一TTT)，但仍编码同一蛋白Phe(F)一Phe(F)，为同
义突变。变异基因型TT的相对危险度较低(RR为0.586)，与鼻咽癌表
型之间关联程度低;非编码区SNP位点C506380A在对照人群和鼻咽
癌患者中变异基因型AA的RR值为0.612，与鼻咽癌表型关联程度不大;
内含子区SNP位点T49984OC的多态类型与鼻咽癌易感的关联程度较高，
基因型Tl，携带者发生鼻咽癌的可能性是是对照人群的4.225倍(95%置
信区间为1.873一9.531)。
上述结果提示丫付2调控区SNP位点K泞2G1990158A和
丫日2G1990398T的变异与鼻咽癌易感的关联程度较高，是鼻咽癌遗传易
感的风险因子。CYPZEI内含子区SNP位点T499840C的变异与鼻咽癌
也有关联，是否能成为鼻咽癌易感的标志或能成为寻找其它真正的鼻咽
癌易感基因的路标还需进一步探讨。
Nasopharyngeal carcinoma (NPC) is a rare tumor in most parts of the world but occurs at relatively high incidence among people of southern China. The epidemiologic investigation indicates that NPC is a multi-gene hereditary disease, which relates to race and familial traits, as well as concerns with oncogenes and/or suppressor genes. The etiology studies demonstrate that environment factors and the infection of Epstein-Barr virus as well as genetic alterations play a very important role in NPC developing. Up till now there hasn't been identified own gene of NPC but some related genes.
Single nucleotide polymorphism (SNP) is a useful genetic marker because of its high density and hereditary stability and the capacity for highly automated analysis. SNP is thought to be a powerful tool for finding the contributions of individual genes to complex, multigene diseases. Actually, genetic variations underline differences in our susceptibility to, or protection from, all kinds of disease. Knowledge of genetic variations also affects patient treatment to some degree.
Using bioinformatics means, 7 genes were picked out to be studied , including the tumour suppressor gene candidates, such as YH1, NPCR and NAG22, EBV receptor CR2 which can guide EBV into lymphocytes, TSG101 which is a suppressor gene and multi-organ metabolic enzyme at the same time, as well as CYP2E1 and GSTm1 which are very important phase I (oxidation) and II (conjugation) metabolic enzymes.
In order to gain SNP from these genes, 27 samples and 5 pools, which originated from the Han nationality and minority of Chinese, were examined by sequence and 102 SNP loci were discovered. There are 46 and 9 SNP in 5'Flank and 5'UTR, respectively; only 14 SNP in coding region are discovered. In 3TJTR and 3'Flank, there are 11 and 14 SNP, respectively. 73 in 102 SNP haven't been reported. 7 in 14 cSNP have moderate or high frequency (the rare allele frequency is from 7.4% to 32.7%), only 2 loci have no changes among amino acids, the rest 5 in 14 SNP have lower frequency (the rare allele gene frequency is just 1.9%), onlylof them has no change.
87 loci of 102 SNP, which allele frequencies exceed 0.01, were analyzed by linkage disequilibrium (LD), the results showed that 83 pairs locus presented highly linkage disequilibrium each other, 21 pairs in CR2, 21 pairs in YH1, 1 pair in NAG22, 9 pairs in TSG101, 29 pairs in NPCR, 13 pairs in GSTml and 12 pairs in CYP2E1, respectively.
In the present study, we investigated the correlation between the polymorphism of the 7 genes and NPC on a total of 238 patients and 286 controls. The PCR-RFLP and tetra-Primer ARMS-PCR analysis were used to evaluate 12 polymorphisms in the coding region of 6 genes, htSNP derived from results by calculating haplotype was also applied to estimate polymorphism in CYP2E1. The relative risk (RR) was estimated by the odds ratio (OR), to determine the association between genotype of these genes and NPC development.
The results of all above mentioned showed that lower allele frequency of YH1, CR2, NAG22 or NPCR could not become an individual marker to analyze the correlation between the polymorphism and NPC.
GSTml C1270533T was discovered for the first time (the rare allele frequency is 22.2%), that the second genetic code in No.96 amino acid appears variation and makes this locus a missense mutation. The genotype displayed suggested there was no association between the phenotype and NPC susceptibility (RR=0.170, 95%CI =0.95-0.306 for homozygote TT).
YH1 G1990158A and YH1 G1990398T are located in regulating region and the rare allele frequency is 22.2% in Chinese. The results indicated that homozygous variant GG in YH1 G1990158A was at a 2.3-fold risk of disease (95% confidence interval = 1.458-3.628). Similarly, homozygous variant GG in YH1 G1990398T was at 3.6-fold risk of developing NPC (95% confidence interval =1.97-6.693).
CYP2E1 T505228A is located at coding region, its third genetic code in the 421th amino acid appears variation, making this locus a synonymous mutation, the R
筛查和验证疾病相关基因的方法不少，而单核苷酸多态性(single nucleotide polymorphism，SNPs)作为第三代遗传标记因其分布密度高、遗传稳定性强和易实现分析的自动化的特性，被认为是目前人类遗传性和遗传相关性疾病的诊断以及群体遗传学的研究、药物的开发和应用等方面最佳检测方法。
本实验采用生物信息学方法搜寻筛查在遗传易感、病毒感染和化学促(致)癌等方面与鼻咽癌发病有密切关系的、具有代表性的7个基因进行SNP研究，其中YH1、NAG22、NPCR是鼻咽癌相关的抑瘤基因的侯选基因，CR2是介导EBV进入淋巴细胞的受体，TSG101是肿瘤抑制基因，同时也是体内广泛分布的一种多脏器代谢酶，CYP2E1及GSTml是体内重要的Ⅰ相代谢酶和Ⅱ相代谢酶的代表。这些基因与鼻咽癌发病机理有不同程度的关联，可以促使我们从不同角度来探讨和加深对鼻咽癌发病机理的认识。
用测序的方法从中华民族27个个体和5个pool中共筛查出具有中华民族特征的SNP102个，其中5′Flank46个，5′UTR9个，Coding14个，Intron18个，3′UTR11个，3′Flank14个。在102个多态位点中，有73
个为首次发现。14个csNP中7个为中高频位点(罕见等位基因频率为
7.40%一32.7%)，其中2个位点无氨基酸改变;余5个为低频位点(罕见
等位基因频率为1.9%)，其中1个位点无氨基酸改变。
对102个SNP多态位点中频率大于0.01、其它数据完整的87个SNP
进行连锁不平衡分析，结果表明有83对位点之间呈高度连锁不平衡尤况2
l对;11了121对;刀且G221对;TSGI019对;刃尸C尺29对;GS乃nl 13
对:CYPZEllZ对。
采用病例一对照的方法在238例鼻咽癌患者和286例正常对照人群
中，用RFLP一PCR、tetra一Pri~ARMS一PCR和测序分型方法对6个基因
(K片了、C尺2、刀摊G22、N尸C尺、TSGIOI和G 57初I)eSNP12个位点、YHI
基因调控区2个SNP位点以及通过单倍型计算获得的CYPZE13个htSNP
位点展开基因分型，用OR值来评估这些基因的基因型与鼻咽癌表型之
间的相对危险度，发现:
用K日了、CRZ、入摊G22、刃尸C尺低频SNP位点(延1 .9%)进行群体
分型实际意义不大，更不能以此单独作为某一种界标。
Gs乃nl C1270533T为首次发现的多态位点(中国人群罕见等位基因
rl，频率为22.2%)，其96位氨基酸的第二位密码子发生了碱基颠换(CGT
一C竹)，使沁g一Leu，导致错义突变。分型结果表明，基因型TT和
GT的RR值分别为0.170和0.605，该位点的表型与鼻咽癌无关联。
KHZ调控区2个SNP位点(中国人群罕见等位基因频率分别为37.0%
和38.9%)，K“2 G199O158A基因型GG携带者患鼻咽癌的危险性是对照
人群的2.3倍(95%置信区间为1.458一3.628);K阿2 G1990398T基因型
GG携带者发生鼻咽癌的可能性是对照人群的3.166倍(95%置信区间为
1 .784一5.619)。
CYPZEI cSNp位点T505228A，其421位氨基酸的第三位密码子发
生了碱基颠换(TTC一TTT)，但仍编码同一蛋白Phe(F)一Phe(F)，为同
义突变。变异基因型TT的相对危险度较低(RR为0.586)，与鼻咽癌表
型之间关联程度低;非编码区SNP位点C506380A在对照人群和鼻咽
癌患者中变异基因型AA的RR值为0.612，与鼻咽癌表型关联程度不大;
内含子区SNP位点T49984OC的多态类型与鼻咽癌易感的关联程度较高，
基因型Tl，携带者发生鼻咽癌的可能性是是对照人群的4.225倍(95%置
信区间为1.873一9.531)。
上述结果提示丫付2调控区SNP位点K泞2G1990158A和
丫日2G1990398T的变异与鼻咽癌易感的关联程度较高，是鼻咽癌遗传易
感的风险因子。CYPZEI内含子区SNP位点T499840C的变异与鼻咽癌
也有关联，是否能成为鼻咽癌易感的标志或能成为寻找其它真正的鼻咽
癌易感基因的路标还需进一步探讨。
Nasopharyngeal carcinoma (NPC) is a rare tumor in most parts of the world but occurs at relatively high incidence among people of southern China. The epidemiologic investigation indicates that NPC is a multi-gene hereditary disease, which relates to race and familial traits, as well as concerns with oncogenes and/or suppressor genes. The etiology studies demonstrate that environment factors and the infection of Epstein-Barr virus as well as genetic alterations play a very important role in NPC developing. Up till now there hasn't been identified own gene of NPC but some related genes.
Single nucleotide polymorphism (SNP) is a useful genetic marker because of its high density and hereditary stability and the capacity for highly automated analysis. SNP is thought to be a powerful tool for finding the contributions of individual genes to complex, multigene diseases. Actually, genetic variations underline differences in our susceptibility to, or protection from, all kinds of disease. Knowledge of genetic variations also affects patient treatment to some degree.
Using bioinformatics means, 7 genes were picked out to be studied , including the tumour suppressor gene candidates, such as YH1, NPCR and NAG22, EBV receptor CR2 which can guide EBV into lymphocytes, TSG101 which is a suppressor gene and multi-organ metabolic enzyme at the same time, as well as CYP2E1 and GSTm1 which are very important phase I (oxidation) and II (conjugation) metabolic enzymes.
In order to gain SNP from these genes, 27 samples and 5 pools, which originated from the Han nationality and minority of Chinese, were examined by sequence and 102 SNP loci were discovered. There are 46 and 9 SNP in 5'Flank and 5'UTR, respectively; only 14 SNP in coding region are discovered. In 3TJTR and 3'Flank, there are 11 and 14 SNP, respectively. 73 in 102 SNP haven't been reported. 7 in 14 cSNP have moderate or high frequency (the rare allele frequency is from 7.4% to 32.7%), only 2 loci have no changes among amino acids, the rest 5 in 14 SNP have lower frequency (the rare allele gene frequency is just 1.9%), onlylof them has no change.
87 loci of 102 SNP, which allele frequencies exceed 0.01, were analyzed by linkage disequilibrium (LD), the results showed that 83 pairs locus presented highly linkage disequilibrium each other, 21 pairs in CR2, 21 pairs in YH1, 1 pair in NAG22, 9 pairs in TSG101, 29 pairs in NPCR, 13 pairs in GSTml and 12 pairs in CYP2E1, respectively.
In the present study, we investigated the correlation between the polymorphism of the 7 genes and NPC on a total of 238 patients and 286 controls. The PCR-RFLP and tetra-Primer ARMS-PCR analysis were used to evaluate 12 polymorphisms in the coding region of 6 genes, htSNP derived from results by calculating haplotype was also applied to estimate polymorphism in CYP2E1. The relative risk (RR) was estimated by the odds ratio (OR), to determine the association between genotype of these genes and NPC development.
The results of all above mentioned showed that lower allele frequency of YH1, CR2, NAG22 or NPCR could not become an individual marker to analyze the correlation between the polymorphism and NPC.
GSTml C1270533T was discovered for the first time (the rare allele frequency is 22.2%), that the second genetic code in No.96 amino acid appears variation and makes this locus a missense mutation. The genotype displayed suggested there was no association between the phenotype and NPC susceptibility (RR=0.170, 95%CI =0.95-0.306 for homozygote TT).
YH1 G1990158A and YH1 G1990398T are located in regulating region and the rare allele frequency is 22.2% in Chinese. The results indicated that homozygous variant GG in YH1 G1990158A was at a 2.3-fold risk of disease (95% confidence interval = 1.458-3.628). Similarly, homozygous variant GG in YH1 G1990398T was at 3.6-fold risk of developing NPC (95% confidence interval =1.97-6.693).
CYP2E1 T505228A is located at coding region, its third genetic code in the 421th amino acid appears variation, making this locus a synonymous mutation, the R
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