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Article(id=1199335101931815557, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1199335100786766058, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2092.2023.0717, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1665331200000, receivedDateStr=2022-10-10, revisedDate=null, revisedDateStr=null, acceptedDate=1678032000000, acceptedDateStr=2023-03-06, onlineDate=1763873370868, onlineDateStr=2025-11-23, pubDate=1709049600000, pubDateStr=2024-02-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763873370868, onlineIssueDateStr=2025-11-23, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763873370868, creator=13701087609, updateTime=1763873370868, updator=13701087609, issue=Issue{id=1199335100786766058, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='2', pageStart='123', pageEnd='244', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763873370596, creator=13701087609, updateTime=1763874072387, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1199338044361896535, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1199335100786766058, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1199338044361896536, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1199335100786766058, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=171, endPage=176, ext={EN=ArticleExt(id=1199335102204445318, articleId=1199335101931815557, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Association between ELL2 polymorphism and susceptibility to pleomorphic adenoma of salivary gland, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To analyze the correlation between the ELL2 gene 1119 T>C polymorphism and the susceptibility to pleomorphic adenoma of the salivary gland. Methods The pedigree of the pleomorphic adenoma family of salivary gland was drawn. The exons of ELL2 gene in 5 members of salivary pleomorphic adenoma family were sequenced. A case-control study was conducted. One hundred and twelve patients with pleomorphic adenoma of the salivary gland who visited the Department of Oral and Maxillofacial Surgery of Shanxi Bethune Hospital from January 2016 to July 2020 were taken as case group, and 176 healthy examinees from January 2019 to January 2020 were taken as control group with age and sex as matching conditions. The 1119 T>C polymorphism of ELL2 genes in the two groups were detected with high resolution melting (HRM) curve. Chi-square test was adopted to analyze the correlation between gene polymorphism and the occurrence of pleomorphic adenoma of the salivary gland, stratified analysis was performed to evaluate the synergistic effect of smoking and genotype, and real time quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression level of ELL2 in individuals with different genotypes. Results The 1119 T>C polymorphism site existed in the exon 8 of ELL2 gene in a family with pleomorphic adenoma of salivary gland. The results of case-control study showed that the genotype frequency of homozygous CC was significantly higher in patients with pleomorphic adenoma of salivary gland than that in the controls (24.1% vs. 11.9%, P=0.002). Homozygous CC was associated with increased risk for developing pleomorphic adenoma of salivary gland (OR=3.059, 95%CI 1.494-6.263) in this cohort. Stratification analysis showed that smoking and 1119C allele cooperated to increase the risk of pleomorphic adenoma of salivary gland (OR=3.200, 95%CI 1.460-7.014). The expression level of ELL2 mRNA in CC genotype was significantly higher than that in individuals with CT or TT genotype (P<0.05). Conclusion The genetic variation of ELL2 may play an important role in the occurrence of pleomorphic adenoma of salivary gland, and smoking combined with the 1119C allele increased the risk of this disease.

, correspAuthors=Zhi-Rong Liu, authorNote=null, correspAuthorsNote=
E-mail:
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目的 分析ELL2基因1119T>C多态性与涎腺多形性腺瘤易感性之间的相关性。方法 绘制涎腺多形性腺瘤家系，对涎腺多形性腺瘤家系中5个成员的ELL2基因外显子进行测序；采用病例对照研究，将2016年1月-2020年7月就诊于山西白求恩医院口腔颌面外科的112例涎腺多形性腺瘤患者作为病例组，以年龄、性别为匹配条件，将2019年1月-2020年1月该院176名健康体检者作为对照组。高分辨熔解曲线(HRM)检测两组ELL2基因1119T>C多态性；采用χ2检验分析基因多态性与涎腺多形性腺瘤发生之间的相关性，分层分析评估吸烟与基因型的协同作用；并采用实时定量反转录聚合酶链反应(RT-PCR)检测不同基因型个体ELL2的表达水平。结果 涎腺多形性腺瘤家系中ELL2基因第8外显子存在1119T>C多态性位点。病例对照研究结果显示，涎腺多形性腺瘤患者该位点纯合子CC基因频率明显高于对照组(24.1% vs. 11.9%，P=0.002)。纯合子CC与涎腺多形性腺瘤发生风险增加相关(OR=3.059，95%CI 1.494~6.263)。分层分析显示，吸烟与1119C等位基因协同作用可增加涎腺多形性腺瘤发生的风险(OR=3.200，95%CI 1.460~7.014)。CC基因型个体ELL2 mRNA表达水平明显高于CT或TT基因型个体(P<0.05)。结论 ELL2基因变异可能在涎腺多形性腺瘤的发生中起重要作用，吸烟联合1119C等位基因可增加涎腺多形性腺瘤的发病风险。

, correspAuthors=刘志荣, authorNote=null, correspAuthorsNote=
刘志荣，E-mail：
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杨思遥，医学硕士，主要从事口腔肿瘤发生机制等方面的研究

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杨思遥，医学硕士，主要从事口腔肿瘤发生机制等方面的研究

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杨思遥，医学硕士，主要从事口腔肿瘤发生机制等方面的研究

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Nat Commun, 2015, 6: 7213., articleTitle=Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma, refAbstract=null)], funds=[Fund(id=1199335109758387037, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, awardId=82272622, language=EN, fundingSource=National Natural Science Foundation of China(82272622), fundOrder=null, country=null), Fund(id=1199335109867438946, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, awardId=82272622, language=CN, fundingSource=国家自然科学基金(82272622), fundOrder=null, country=null), Fund(id=1199335109997462381, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, awardId=2017SY045, language=EN, fundingSource=Graduate Excellent Innovation Project in Shanxi Province(2017SY045), fundOrder=null, country=null), Fund(id=1199335110144263030, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, awardId=2017SY045, language=CN, fundingSource=山西省研究生优秀创新项目(2017SY045), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1199335103383044758, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, xref=1, ext=[AuthorCompanyExt(id=1199335103391433367, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, companyId=1199335103383044758, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Stomatology, Shanxi Bethune Hospital/Tongji Shanxi Hospital, Shanxi Academy of Medical Sciences/Third Hospital of Shanxi Medical University, Taiyuan, Shanxi 030032, China), AuthorCompanyExt(id=1199335103399821976, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, companyId=1199335103383044758, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1山西白求恩医院/山西医学科学院同济山西医院/山西医科大学第三医院口腔科，山西太原 030032)]), AuthorCompany(id=1199335103471125146, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, xref=2, ext=[AuthorCompanyExt(id=1199335103479513755, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, companyId=1199335103471125146, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi 030001, China), AuthorCompanyExt(id=1199335103483708060, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, companyId=1199335103471125146, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2山西医科大学基础医学院，山西太原 030001)])], figs=[ArticleFig(id=1199335106755265272, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=EN, label=Fig.1, caption=A pedigree of pleomorphic adenoma of the salivary gland, figureFileSmall=2tDIFxNWm5o4+E4gfLV/mg==, figureFileBig=vX4MJV3XziKipWUTg9n01Q==, tableContent=null), ArticleFig(id=1199335106822374139, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=CN, label=图1, caption=一例涎腺多形性腺瘤家系

箭头示先证者，阴影示患者，正方形示男性，圆形示女性

, figureFileSmall=2tDIFxNWm5o4+E4gfLV/mg==, figureFileBig=vX4MJV3XziKipWUTg9n01Q==, tableContent=null), ArticleFig(id=1199335107090809607, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=EN, label=Fig.2, caption=Genotyping and sequencing of ELL2 exon 8, figureFileSmall=+Gs1/vCfDcAohNDQGX+rNQ==, figureFileBig=sonFFmiFMdrSdWppsK37Yw==, tableContent=null), ArticleFig(id=1199335107191472907, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=CN, label=图2, caption=ELL2外显子8基因分型和测序

HRM. 高分辨熔解曲线；A. 5个家族成员第8外显子测序结果；B. HRM结果(蓝色曲线为TT基因型，灰色曲线为CT基因型，红色曲线为CC基因型)；C. 扩增产物的测序结果

, figureFileSmall=+Gs1/vCfDcAohNDQGX+rNQ==, figureFileBig=sonFFmiFMdrSdWppsK37Yw==, tableContent=null), ArticleFig(id=1199335107275358992, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=EN, label=Fig.3, caption=Expression levels of ELL2 mRNA in different genotypes, figureFileSmall=A5W48qA+cpLfr6kyjb/ojQ==, figureFileBig=A6S8uFSNwNeRPlxZA2kc5g==, tableContent=null), ArticleFig(id=1199335107355050775, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=CN, label=图3, caption=不同基因型ELL2 mRNA的表达水平, figureFileSmall=A5W48qA+cpLfr6kyjb/ojQ==, figureFileBig=A6S8uFSNwNeRPlxZA2kc5g==, tableContent=null), ArticleFig(id=1199335107506045725, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=EN, label=Tab.1, caption=

Primer sequences for PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
名称序列
ELL2外显子8(扩增)上游：5'-CTGCGGCTGCTGCCATCC-3'
下游：5'-GAGATGGGCAGATAGGTTGAAGG-3'
ELL2外显子(测序)上游：5'-CACCTGACGAACAGAGTACC-3'
下游：5'-TGTCTTGCTGGTCCTCATA-3'
ELL2(q-PCR引物)上游：5'-ACAAGAATTTAATTCCTTTTCGACC-3'
下游：5'-GAGCTGGAGAATGTTTGCTGG-3'
GAPDH上游；5'-GAACGGGAAGCTCACTGG-3'
下游：5'-GCCTGCTTCACCACCTTCT-3'
), ArticleFig(id=1199335107636069156, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=CN, label=表1, caption=

PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
名称序列
ELL2外显子8(扩增)上游：5'-CTGCGGCTGCTGCCATCC-3'
下游：5'-GAGATGGGCAGATAGGTTGAAGG-3'
ELL2外显子(测序)上游：5'-CACCTGACGAACAGAGTACC-3'
下游：5'-TGTCTTGCTGGTCCTCATA-3'
ELL2(q-PCR引物)上游：5'-ACAAGAATTTAATTCCTTTTCGACC-3'
下游：5'-GAGCTGGAGAATGTTTGCTGG-3'
GAPDH上游；5'-GAACGGGAAGCTCACTGG-3'
下游：5'-GCCTGCTTCACCACCTTCT-3'
), ArticleFig(id=1199335107749315367, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=EN, label=Tab.2, caption=

Comparison of general characters between patients with pleomorphic adenoma of salivary gland and control group [n(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
指标

病例组
(n=112)

对照组
(n=176)

P
性别0.383
男60(53.6)85(42.3)
女52(46.4 )91(51.7)
年龄(岁)0.126
<6037(33.0)74(42.0)
≥6075(67.0)102(58.0)
组织分型
多形性腺瘤78(69.6)
癌前多形性腺瘤17(15.2)
癌肉瘤10(8.9)
转移性多形性腺瘤7(6.3)
吸烟情况0.013
吸烟67(59.8)79(44.9)
不吸烟45(40.2)97(55.1)
), ArticleFig(id=1199335107900310316, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=CN, label=表2, caption=

涎腺多形性腺瘤患者与对照组的一般特征比较[例(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
指标

病例组
(n=112)

对照组
(n=176)

P
性别0.383
男60(53.6)85(42.3)
女52(46.4 )91(51.7)
年龄(岁)0.126
<6037(33.0)74(42.0)
≥6075(67.0)102(58.0)
组织分型
多形性腺瘤78(69.6)
癌前多形性腺瘤17(15.2)
癌肉瘤10(8.9)
转移性多形性腺瘤7(6.3)
吸烟情况0.013
吸烟67(59.8)79(44.9)
不吸烟45(40.2)97(55.1)
), ArticleFig(id=1199335108047110962, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=EN, label=Tab.3, caption=

The genotype frequencies of ELL2 T1119C in patients with pleomorphic adenoma of salivary gland and control group [n(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
基因型

病例组
(n=112)

对照组
(n=176)

POR(95%CI)
TT29(25.9)69(39.2)1(参考值)
CT56(50.0)86(48.9)0.1171.549(0.895~2.683)
CC27(24.1)21(11.9)0.0023.059(1.494~6.263)
), ArticleFig(id=1199335108193911608, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=CN, label=表3, caption=

涎腺多形性腺瘤患者与对照组的ELL2 T1119C基因型频率[例(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
基因型

病例组
(n=112)

对照组
(n=176)

POR(95%CI)
TT29(25.9)69(39.2)1(参考值)
CT56(50.0)86(48.9)0.1171.549(0.895~2.683)
CC27(24.1)21(11.9)0.0023.059(1.494~6.263)
), ArticleFig(id=1199335108353295171, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=EN, label=Tab.4, caption=

Distribution of ELL2 T1119C alleles and genotypes in different pathologic types

, figureFileSmall=null, figureFileBig=null, tableContent=
病理类型基因型[例(%)]P等位基因(%)P
TTCTCCTC
多形性腺瘤20(25.6)40(51.3)18(23.1)151.348.71
癌前多形性腺瘤5(29.4)9(52.9)3(17.6)0.87455.944.10.573
癌肉瘤2(20.0)4(40.0)4(40.0)0.50840.060.00.502
转移性多形性腺瘤2(28.6)3(42.8)2(28.6)0.90850.050.00.100*
), ArticleFig(id=1199335108466541382, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=CN, label=表4, caption=

ELL2 T1119C等位基因及基因型在不同病理类型中的分布

, figureFileSmall=null, figureFileBig=null, tableContent=
病理类型基因型[例(%)]P等位基因(%)P
TTCTCCTC
多形性腺瘤20(25.6)40(51.3)18(23.1)151.348.71
癌前多形性腺瘤5(29.4)9(52.9)3(17.6)0.87455.944.10.573
癌肉瘤2(20.0)4(40.0)4(40.0)0.50840.060.00.502
转移性多形性腺瘤2(28.6)3(42.8)2(28.6)0.90850.050.00.100*
), ArticleFig(id=1199335108575593293, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=EN, label=Tab.5, caption=

Stratification analysis of the strength of the association between ELL2 T1119C polymorphism and pleomorphic adenoma

, figureFileSmall=null, figureFileBig=null, tableContent=
吸烟情况CTPOR(95%CI)
不吸烟(n=142)
病例组(n=45)0.410.490.5191.183(0.710~1.972)
对照租(n=97)0.370.63
吸烟(n=146)
病例组(n=67)0.540.460.0012.180(1.361~3.491)
对照组(n=79)0.350.65
), ArticleFig(id=1199335108667867989, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1199335101931815557, language=CN, label=表5, caption=

ELL2 T1119C多态性与多形性腺瘤相关性强度的分层分析

, figureFileSmall=null, figureFileBig=null, tableContent=
吸烟情况CTPOR(95%CI)
不吸烟(n=142)
病例组(n=45)0.410.490.5191.183(0.710~1.972)
对照租(n=97)0.370.63
吸烟(n=146)
病例组(n=67)0.540.460.0012.180(1.361~3.491)
对照组(n=79)0.350.65
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ELL2基因多态性与涎腺多形性腺瘤易感性的相关性分析
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杨思遥 1 , 王媛媛 1 , 刘建兵 2 , 刘志荣 1, *
解放军医学杂志 | 临床研究 2024,49(2): 171-176
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解放军医学杂志 | 临床研究 2024, 49(2): 171-176
ELL2基因多态性与涎腺多形性腺瘤易感性的相关性分析
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杨思遥1, 王媛媛1, 刘建兵2, 刘志荣1, *
作者信息
  • 1山西白求恩医院/山西医学科学院同济山西医院/山西医科大学第三医院口腔科，山西太原 030032
  • 2山西医科大学基础医学院，山西太原 030001

    • 杨思遥，医学硕士，主要从事口腔肿瘤发生机制等方面的研究

通讯作者:

刘志荣，E-mail：
Association between ELL2 polymorphism and susceptibility to pleomorphic adenoma of salivary gland
Si-Yao Yang1, Yuan-Yuan Wang1, Jian-Bing Liu2, Zhi-Rong Liu1, *
Affiliations
  • 1Department of Stomatology, Shanxi Bethune Hospital/Tongji Shanxi Hospital, Shanxi Academy of Medical Sciences/Third Hospital of Shanxi Medical University, Taiyuan, Shanxi 030032, China
  • 2School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi 030001, China
出版时间: 2024-02-28 doi: 10.11855/j.issn.0577-7402.2092.2023.0717
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目的 分析ELL2基因1119T>C多态性与涎腺多形性腺瘤易感性之间的相关性。方法 绘制涎腺多形性腺瘤家系，对涎腺多形性腺瘤家系中5个成员的ELL2基因外显子进行测序；采用病例对照研究，将2016年1月-2020年7月就诊于山西白求恩医院口腔颌面外科的112例涎腺多形性腺瘤患者作为病例组，以年龄、性别为匹配条件，将2019年1月-2020年1月该院176名健康体检者作为对照组。高分辨熔解曲线(HRM)检测两组ELL2基因1119T>C多态性；采用χ2检验分析基因多态性与涎腺多形性腺瘤发生之间的相关性，分层分析评估吸烟与基因型的协同作用；并采用实时定量反转录聚合酶链反应(RT-PCR)检测不同基因型个体ELL2的表达水平。结果 涎腺多形性腺瘤家系中ELL2基因第8外显子存在1119T>C多态性位点。病例对照研究结果显示，涎腺多形性腺瘤患者该位点纯合子CC基因频率明显高于对照组(24.1% vs. 11.9%，P=0.002)。纯合子CC与涎腺多形性腺瘤发生风险增加相关(OR=3.059，95%CI 1.494~6.263)。分层分析显示，吸烟与1119C等位基因协同作用可增加涎腺多形性腺瘤发生的风险(OR=3.200，95%CI 1.460~7.014)。CC基因型个体ELL2 mRNA表达水平明显高于CT或TT基因型个体(P<0.05)。结论 ELL2基因变异可能在涎腺多形性腺瘤的发生中起重要作用，吸烟联合1119C等位基因可增加涎腺多形性腺瘤的发病风险。

涎腺多形性腺瘤  /  基因，ELL2  /  单核苷酸多态性  /  遗传变异

Objective To analyze the correlation between the ELL2 gene 1119 T>C polymorphism and the susceptibility to pleomorphic adenoma of the salivary gland. Methods The pedigree of the pleomorphic adenoma family of salivary gland was drawn. The exons of ELL2 gene in 5 members of salivary pleomorphic adenoma family were sequenced. A case-control study was conducted. One hundred and twelve patients with pleomorphic adenoma of the salivary gland who visited the Department of Oral and Maxillofacial Surgery of Shanxi Bethune Hospital from January 2016 to July 2020 were taken as case group, and 176 healthy examinees from January 2019 to January 2020 were taken as control group with age and sex as matching conditions. The 1119 T>C polymorphism of ELL2 genes in the two groups were detected with high resolution melting (HRM) curve. Chi-square test was adopted to analyze the correlation between gene polymorphism and the occurrence of pleomorphic adenoma of the salivary gland, stratified analysis was performed to evaluate the synergistic effect of smoking and genotype, and real time quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression level of ELL2 in individuals with different genotypes. Results The 1119 T>C polymorphism site existed in the exon 8 of ELL2 gene in a family with pleomorphic adenoma of salivary gland. The results of case-control study showed that the genotype frequency of homozygous CC was significantly higher in patients with pleomorphic adenoma of salivary gland than that in the controls (24.1% vs. 11.9%, P=0.002). Homozygous CC was associated with increased risk for developing pleomorphic adenoma of salivary gland (OR=3.059, 95%CI 1.494-6.263) in this cohort. Stratification analysis showed that smoking and 1119C allele cooperated to increase the risk of pleomorphic adenoma of salivary gland (OR=3.200, 95%CI 1.460-7.014). The expression level of ELL2 mRNA in CC genotype was significantly higher than that in individuals with CT or TT genotype (P<0.05). Conclusion The genetic variation of ELL2 may play an important role in the occurrence of pleomorphic adenoma of salivary gland, and smoking combined with the 1119C allele increased the risk of this disease.

salivary gland pleomorphic adenoma  /  gene, ELL2  /  single nucleotide polymorphism  /  genetic variation
杨思遥, 王媛媛, 刘建兵, 刘志荣. ELL2基因多态性与涎腺多形性腺瘤易感性的相关性分析. 解放军医学杂志, 2024 , 49 (2) : 171 -176 . DOI: 10.11855/j.issn.0577-7402.2092.2023.0717
Si-Yao Yang, Yuan-Yuan Wang, Jian-Bing Liu, Zhi-Rong Liu. Association between ELL2 polymorphism and susceptibility to pleomorphic adenoma of salivary gland[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (2) : 171 -176 . DOI: 10.11855/j.issn.0577-7402.2092.2023.0717
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涎腺多形性腺瘤是常见的涎腺肿瘤之一，具有多向分化的特点，异质性高，部分涎腺多形性腺瘤可发生恶性转化[1-2]。涎腺多形性腺瘤发生多向分化和恶性转化的机制尚不清楚，环境因素(如电离辐射)、吸烟、饮酒和激素水平与该病的发生有关，但该病的分子遗传学变化目前尚不清楚。研究发现，涎腺多形性腺瘤相关基因常有重排和拷贝数变异，涉及转录因子多形性腺瘤基因1(pleomorphic adenoma gene 1，PLAG1)和高迁移率族AT Hook蛋白2(high-mobility group AT-hook 2，HMGA2)[3-4]。1997年，Shilatifard等[5]发现，转录因子家族的新成员——RNA聚合酶2延伸因子(elongation factor for RNA polymerase Ⅱ 2，ELL2)基因位于5q15，有12个外显子。ELL2在浆细胞分泌免疫球蛋白中起核心作用，能有效地指导mRNA的剪接加工，调节其转录活性[6-7]。ELL2可调节细胞的生长和增殖，在人类恶性肿瘤的发生发展中发挥重要作用[8-9]。有研究发现，ELL2是多发性骨髓瘤的易感基因且rs3888189-C等位基因与涎腺癌的发生有关[10]；ELL2是雄激素受体(AR)阴性前列腺癌细胞生存和增殖所需的潜在致癌蛋白[11]。本研究对腮腺多形性腺瘤家系5个成员的ELL2基因外显子进行了扩增和测序，并招募了112例涎腺多形性腺瘤患者及176名健康对照者检测其ELL2基因1119T>C多态性，旨在阐明1119T>C多态性与涎腺多形性腺瘤发生的相关性。
1 资料与方法
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1.1 研究对象
将2015年11月山西白求恩医院收治的1例55岁男性腮腺多形性腺瘤患者作为先证者，收集该患者的亲属信息。采用病例对照研究，纳入2016年1月-2020年7月在山西白求恩医院口腔颌面外科就诊的112例涎腺多形性腺瘤患者(病例组)及2019年1月-2020年1月本院的176名健康体检者(对照组)进行验证分析。纳入标准：(1)按Seifert等[12]的方法，术后经组织病理检查确诊为涎腺多形性腺瘤；(2)临床资料完整；(3)进行门诊或电话随访；(4)签署知情同意书。排除标准：合并其他肿瘤或严重心、肺、肾功能障碍。本研究获山西白求恩医院伦理委员会审批(审批号：YXLL-2022-046)。
1.2 主要试剂及仪器
全血基因组DNA提取试剂盒购自美国Omega Bio-Tek公司，RNA提取试剂RNAiso、2×PCR Premix Taq酶购自日本TaKaRa公司，LC-Green饱和荧光染料购自美国Idaho Technology公司。高分辨熔解曲线分析仪LightScannerTM Instrument 96购自美国Idaho Technology公司，实时荧光定量PCR仪购自美国Thermo Fisher公司。
1.3 资料收集
收集腮腺多形性腺瘤患者及其亲属信息，绘制系谱图；收集病例组和对照组的一般资料，包括性别、年龄、吸烟情况、腺瘤病理组织分型等，其中吸烟情况通过问卷调查方式获得，参考Franco等[13]吸烟情况以香烟总数计算，曾经吸烟定义为每天吸烟≥1包、持续1年以上；不吸烟被定义为从不吸烟，或者每天吸烟≥1包、持续1年以上，但戒烟超过6个月。
1.4 全血基因组DNA提取及单核苷酸多态性(SNP)分型
采集家系成员Ⅱ4、Ⅱ5、Ⅱ7、Ⅲ11、Ⅲ12，以及112例涎腺多形性腺瘤患者和176名健康对照的外周血约2 ml，采用全血基因组DNA提取试剂盒提取全血DNA。使用Primer Premier 5软件设计引物，用于扩增ELL2外显子8及测序的引物见表1。采用高分辨熔解曲线(high resolution melting，HRM)对ELL2 1119T>C进行分型。PCR体系包含：基因组DNA 0.1 μg，上下游引物各0.1 μl(10 pmol/μl)，2×PCR Premix Taq酶5 μl，高低温内标0.1 μl，LC-Green饱和荧光染料1.0 μl，蒸馏水加至10 μl。扩增条件：95 ℃预变性3 min；95 ℃变性30 s，58 ℃退火30 s，72 ℃延伸6 s，共35个循环；72 ℃延伸7 min；95 ℃变性30 s，24 ℃退火4 min。PCR扩增产物使用LightScanner™ Instrument 96自动进行基因分型。每个基因型随机抽取5个样本，采用测序引物进行PCR扩增，扩增产物送生工生物(中国上海)进行测序，确定HRM基因分型结果。
1.5 实时定量RT-PCR检测不同基因型个体ELL2表达水平
为明确1119T>C位点不同基因型个体是否影响ELL2基因的表达，使用RNAiso试剂从患者外周血中提取总RNA，取1 μg RNA反转录，采用实时定量PCR (quantitative real-time PCR)检测ELL2基因的表达水平，以GAPDH为参照，引物序列见表1。对每个样品重复3次，并测定平均Ct值，以2-ΔΔCt表示ELL2的相对表达量。
1.6 指标分析
分析病例组与对照组年龄、性别和是否吸烟的差异，以及吸烟与涎腺多形性腺瘤发病风险的关系。根据病例组与对照组的基因型频率：(1)进行Hardy-Weinberg遗传平衡检验，并检验ELL2 1119T>C各基因型与涎腺多形性腺瘤的相关性及其在涎腺多形性腺瘤不同组织分型中的分布；(2)计算两组中吸烟与不吸烟者的等位基因C和T的基因频率，并将是否吸烟作为分层因素，分析ELL2 T1119C等位基因与吸烟是否存在协同作用；(3)比较不同基因型个体外周血ELL2 mRNA表达水平的差异。
1.7 统计学处理
采用SPSS 17.0软件进行统计分析。计数资料以例(%)表示，组间比较采用χ2检验；计量资料呈正态分布时以$\bar{x}±s$表示，组间比较采用t检验，呈非正态分布时组间比较采用Wilcoxon秩和检验。P<0.05为差异有统计学意义。
2 结果
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2.1 涎腺多形性腺瘤患者家系情况
涎腺多形性腺瘤患者的家系谱如图1所示，55岁患者Ⅱ7为先证者，该家族中有5例患者。其中，Ⅱ5为黏液表皮样癌，其他患者为唾液腺良性腺瘤。家系中5位成员(Ⅱ4、Ⅱ5、Ⅱ7、Ⅲ11、Ⅲ12)进行了外显子8扩增和测序。
2.2 两组一般特征比较
病例组与对照组性别、年龄比较差异无统计学意义(P>0.05)，但病例组的吸烟比例高于对照组(P=0.013)(表2)，吸烟可增加涎腺多形性腺瘤的发病风险(OR=1.828，95%CI 1.131~2.956)。
2.3 ELL2 1119T>C多态性与涎腺多形性腺瘤发生的相关性
对该家族5个成员ELL2外显子的测序结果显示，除第8外显子在不同个体中具有TT、CT和CC基因型外，其余序列一致(图2A)。1119T>C位点可能是一个SNP位点。随后在112例患者和176名健康对照者中扩增了第8外显子T1119C位点，采用HRM法对该位点进行自动基因分型，每个基因型随机抽取5个样本进行测序，结果显示HRM法对于TT、CT或CC基因型分型与测序结果一致(图2B、C)。通过Hardy-Weinberg遗传平衡检验，对照组为遗传平衡群体(P>0.05)；对照组最小等位基因频率(minor allele frequency，MAF)=0.36；基因型频率分析结果显示，涎腺多形性腺瘤患者中纯合子CC的比例明显高于对照组(P=0.002)；纯合子CC与涎腺多形性腺瘤发生风险增加相关(OR=3.059，95%CI 1.494~6.263，表3)。
2.4 ELL2 1119T>C多态性在涎腺多形性腺瘤不同病理类型中的分布
对112例涎腺多形性腺瘤患者的病理类型进行分析，并比较T1119C等位基因及基因型在不同病理类型中的分布情况，结果显示不同病理类型间T1119C等位基因及基因型差异无统计学意义(P>0.05，表4)。
2.5 ELL2 1119C多态性与多形性腺瘤相关性强度的分层分析
分层分析结果显示，吸烟与C等位基因协同作用可增加涎腺多形性腺瘤的发病风险(OR=2.180，95%CI 1.361~3.491，P=0.001，表5)。
2.6 T1119C不同基因型个体外周血ELL2的表达水平
实时定量RT-PCR法检测结果显示，CC基因型ELL2 mRNA表达水平明显高于CT(P=0.035)或TT(P=0.003)基因型个体(图3)。
3 讨论
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涎腺多形性腺瘤缺乏特异性的分子标志物，其多向分化及恶性转化的机制尚不明确。本研究对一个涎腺多形性腺瘤家族的5个成员ELL2外显子进行测序后发现，第8外显子中存在一个新的SNP位点：1119T>C，该位点可使ELL2基因第373位密码子由CCT变为CCC(p. Pro373Pro)，为同义突变。5例家族成员中有3例为CC基因型，1例患者和1例健康成员在该位点为CT基因型。因此，本研究招募了112例涎腺多形性腺瘤患者和176名健康对照者，利用HRM法分析该位点多态性，并进行基因分型。结果显示，该位点的MAF为0.36，属于SNP位点。ELL2的1119-C等位基因与涎腺多形性腺瘤相关，吸烟与C等位基因协同作用可增加涎腺多形性腺瘤的发病风险。HRM结果未显示该位点的不同基因型与涎腺多形性腺瘤的不同病理类型有关。
外显子中的一些同义突变也称为沉默突变。虽然，本研究ELL2中的1119T>C为同义突变，但患者中CC基因型的频率明显高于对照组，提示ELL2 1119 T>C位点不同基因型可影响ELL2基因的表达。一般来说，外显子发生同义突变会导致选择性剪接或翻译效率的改变，从而影响基因的表达水平。Ando等[14]报道了mabA(g609a)的沉默突变将突变附近的区域转化为抑制素α亚单位(inhibin subunit alpha，inhA)基因的一个替代启动子，导致异烟肼(isoniazide，INH)的inhA靶基因表达上调，mabA(g609a)沉默突变是INH耐药的一种新机制。外显子的沉默突变也可能导致外显子跳跃，Joshi等[15]报道了一例45岁的肌肉萎缩患者，在ANO5中含有沉默突变Leu115Leu(c.345G>A)；这种突变导致了选择性剪接，cDNA分析显示存在6号外显子跳跃，与肌营养不良发生相关。Ogasawara等[16]也报道了Rh血型D抗原(Rh blood group D antigen，RHD)基因发生960 G>A同义突变，因而影响了基因的可变剪接，降低了D抗原的表达和外显子7的保留。
ELL2促进编码免疫球蛋白重链复合体(IgH)基因的多聚腺苷酸化和外显子跳跃。研究发现，低ELL2表达导致分泌型特异性免疫球蛋白重链mRNA表达丰度降低。ELL2蛋白通过刺激IgH基因启动子近端poly(A)位点偏好和外显子跳跃，从而促进分泌型IgH mRNA的转录后加工。因此，ELL2通过增强非一致剪接位点的外显子跳跃和促进弱启动子近端poly(A)位点的使用，从而独特地影响IgH前mRNA的加工[17]，并在某些肿瘤中促进细胞恶性转化[18]。对良性唾液腺肿瘤的蛋白质组学研究发现，IgH与细胞凋亡、细胞增殖相关蛋白的过度表达有关[19]，分泌型免疫球蛋白重链表达谱对于阐明涎腺多形性腺瘤向恶性肿瘤转变的机制具有重要意义。大量研究发现，浆细胞分布、免疫球蛋白表达及免疫应答在涎腺多形性腺瘤的发生及恶性转化中发挥重要作用[20-21]。此外，肿瘤源性IgG的高表达与恶性肿瘤的发生发展呈正相关[22]。Swaminathan等[23]发现，ELL2的Thr298Ala错义变体可增加多发性骨髓瘤的发生风险；Wang等[11]发现，ELL2的缺失突变可诱导小鼠前列腺上皮内瘤变；在AR阴性前列腺癌细胞中ELL2可促进前列腺癌细胞增殖，是AR阴性前列腺癌细胞生存和增殖所需的潜在致癌蛋白。本研究RT-PCR检测发现，CC基因型个体ELL2 mRNA的表达水平明显高于CT和TT基因型个体。以上结果均表明，ELL2的沉默突变可能导致ELL2表达升高，并可能通过促进Ig或其他相关基因的选择性剪接来改变Ig等相关基因的表达水平，这些改变对多形性腺瘤的发生和恶性转化至关重要。
综上所述，本研究发现，ELL2 1119C等位基因与涎腺多形性腺瘤相关，吸烟与C等位基因协同作用可增加涎腺多形性腺瘤的发病风险，ELL2基因变异可能在涎腺多形性腺瘤的发生中起重要作用。由于涎腺多形性腺瘤患者术后瘤体样本量有限，本研究未能对ELL2不同变异体腺瘤的ELL2蛋白表达水平进行检测。后续需进一步通过构建ELL2不同变异体，在细胞水平及动物水平进一步研究ELL2蛋白表达水平及其对下游相关基因表达调控的影响，从而阐明ELL2的1119T >C变异引起ELL2表达升高的机制，以及引起涎腺多形性腺瘤发生的分子机制。
基金
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  • 国家自然科学基金(82272622)
  • 山西省研究生优秀创新项目(2017SY045)
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doi: 10.11855/j.issn.0577-7402.2092.2023.0717
  • 接收时间：2022-10-10
  • 首发时间：2025-11-23
  • 出版时间：2024-02-28
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  • 收稿日期：2022-10-10
  • 录用日期：2023-03-06
基金
National Natural Science Foundation of China(82272622)
国家自然科学基金(82272622)
Graduate Excellent Innovation Project in Shanxi Province(2017SY045)
山西省研究生优秀创新项目(2017SY045)
作者信息
    1山西白求恩医院/山西医学科学院同济山西医院/山西医科大学第三医院口腔科，山西太原 030032
    2山西医科大学基础医学院，山西太原 030001

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species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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