摘要
目的
宫颈癌是女性中第二大恶性肿瘤。高危型HPV(human papillomavirus,HPV)16持续感染是宫颈癌发生的主要但非唯一病因。叶酸是一碳单位供体,参与DNA甲基化,与宫颈癌发生有着密切的关系。近年来有资料表明脆性组氨酸三联体(FHIT)基因CpG岛高甲基化与宫颈癌发生有关,且HPV16常常整合到FHIT基因的脆弱位点处,提示二者可能存在协同作用,但尚未见相关报道。本次研究诣在界定HPV16感染的前提条件下,探讨叶酸、FHIT基因CPG岛甲基化在宫颈病变中的作用及其可能的交互作用。
方法
采用以医院为基础的病例-对照研究,选择山西医科大学第二临床医院2008年1月-10月,经病理学确诊的、未经放疗与化疗的、新发的宫颈病变病例低度鳞状上皮内病变(LSIL)40例和高度鳞状上皮内病变(HSIL)49例和宫颈鳞癌(SCC)19例作为病例组;对照组为同期就诊的与病例无血缘关系,在年龄、民族和居住地相同的慢性宫颈炎患者108例。全部研究对象均在知情同意下进行研究。对全部研究对象的空腹静脉晨血采用RIA方法测定血清叶酸水平;手术活检组织采用PCR方法检测HPV16的感染情况和MSP方法检测FHIT基因CPG岛的甲基化。使用SPSS13.0,正态分布计量资料用t检验,偏态分布用Kruskal-wallis和Nemeny秩和检验;计数资料采用χ2检验和趋势χ2检验;交互作用采用叉生析。
结果
1.血清叶酸、HPV16与宫颈病变关系
(1)血清叶酸与宫颈病变关系
血清叶酸含量在HSIL组(1.69±0.42 ng/ml)和SCC组(1.36±1.66 ng/ml)低于对照组(3.09±1.98ng/ml),经Kruskal-wallis和Nemenyi秩和检验,HSIL组和SCC组与对照组差别有统计学意义(H=58.044,P=0.000;H=70.479,P=0.000)。
(2)HPV16与宫颈病变关系:
HPV16阳性率在HSIL组(42.9%)和SCC组(56.1%)高于对照组(29.6%),差别有统计学意义(χ2=2.64,P=0.033;χ2=8.02,P=0.005)。
(3)血清叶酸和HPV16交互作用与宫颈病变关系
采用叉生分析显示,血清叶酸缺乏同时HPV16阳性者患SCC的危险(OR=31.31)高于单独HPV16阳性者患SCC的危险(OR=1.95)和单独血清叶酸缺乏者患SCC的危险(OR=5.69)。
2.血清叶酸和FHIT基因CPG岛甲基化与宫颈病变关系
(1)血清叶酸与FHIT基因CPG岛甲基化的关系
FHIT基因CPG岛甲基化率在血清叶酸含量<2.30ng/ml组(31.7%)高于叶酸含量≥2.31ng/ml组(2.2%),差别有统计学意义(χ2=29.22,P=0.000),OR值为20.47,95%CI:4.80-87.32。
(2)FHIT基因CPG岛甲基化与宫颈病变关系
FHIT基因CPG岛甲基化率在LSIL组(12.5%),HSIL组(44.9%)和SCC组(63.2%)均大于对照组(2.85%),差别有统计学意义(χ2=5.40,P=0.020;χ2=44.67,P=0.000;χ2 =56.55,P=0.000);OR值分别为5.0,28.52和60.00;95%CI分别为(1.14-22.00,7.94-102.39和13.68-263.18);FHIT基因CPG岛甲基化率随组织学分级增高而增高。
(3)血清叶酸和FHIT基因CPG岛甲基化的交互作用与宫颈病变关系
采用叉生分析显示,血清叶酸缺乏同时FHIT基因CPG岛高甲基化者患SCC的危险(OR=8.33)高于单独FHIT基因CPG岛高甲基化者患SCC的危险(OR=1.39)和单独血清叶酸缺乏者患SCC的危险(OR=1.53)。
(4)HPV16和FHIT基因CPG岛甲基化的交互作用与宫颈病变关系
采用叉生分析显示,HPV16阳性同时FHIT基因CPG岛高甲基化者患SCC的危险(OR=63.13)高于单独FHIT基因CPG岛高甲基化者患SCC的危险(OR=18.94)和单独HPV16阳性者患SCC的危险(OR=9.47)。且单独FHIT基因CPG岛高甲基化患宫颈病变的危险要大于单独HPV16阳性患宫颈病变的危险。
结论
1.机体血清叶酸缺乏,HPV16阳性是宫颈病变发生的危险因素,二者在宫颈病变发生中可能存在协同作用。
2.血清叶酸缺乏和FHIT基因CPG岛高甲基化有关,FHIT基因CPG岛高甲基化可增加宫颈病变发生的危险。
3.血清叶酸缺乏同时FHIT基因CPG岛高甲基化在宫颈病变发生中可能存在协同作用;HPV16阳性同时FHIT基因CPG岛高甲基化在宫颈病变发生中可能存在协同作用。单独FHIT基因CPG岛高甲基化患病的危险可能大于单独HPV16阳性患病的危险。
Objective
The cervix cancer is the second malignant tumor in woman.High-risk HPV16 infection is major and non unique reason of cervix cancer.Folic acid being donor of one carbon unit that participate DNA methylation is closely related to cervix cancer.In the recently years the datas show hypermethylation of FHIT gene CpG island is correlated with cervix cancer and HPV16 is integrated into the fragile sites of FHIT gene,that possibly have interaction,but we don’t have seen correlated report.The study is premise of HPV16 infection to discuss effect of folic acid and FHIT gene CpG island methylation in cervical lesions and their possible interaction.
Methods
A hospital-based case-control study was conducted in The Second Clinical Hospital of Shanxi Medical University from Jane 2008 to December,the study included pathology definite,nulli-radiotherapy,nulli-chemotherapy and new cervical lesions cases 108:LSIL 40 cases,HSIL 49 cases and SCC 19 cases and 108 controls of chronic cervicitis from the same time without blood relationship with the cases with the same age,ethnic and place of residence.All subjects were informed consent for research.Serum folic acid in blood samples was measured using RIA and HPV16 from surgical biopsy was gained by PCR and FHIT gene CpG island methylation was detected by MSP for all the subjects.Statistical analysis was used by the SPSS13.0,T-test was used by quantitative data in normal distribution;Kruskal-wallis and Nemenyi were used by the skewed distribution;χ2 test andχ2 trend test were used by qualitative data;Crossover analysis was used by interaction.
Results
1. Association between serum folic acid, HPV16 and cervical lesions
(1) Serum folic acid and cervical lesions
Serum folic acid level in HISL(1.69±0.42ng/ml) and SCC(1.36±1.664ng/ml)is lower than that in control (3.09±1.98ng/ml);Using Kruskal-wallis and Nemenyi testing,there is difference between HSIL,SCC and control in serum folic acid level(H=58.044,P=0.000;H=70.479, P=0.000).
(2) HPV16 and cervical lesions
HPV16 infection rate in HSIL(42.9%) and SCC(56.1%) is higher than that in control (29.6%),there is difference between HSIL, SCC and control(χ2=2.64,P=0.033;χ2=8.02,P=0.005).
(3) Serum folic acid and HPV16 were associated with cervical lesions
The results of Crossover analysis show that the risk of folic acid deficiency and HPV16 infection in SCC(OR=31.31) is higher than that when HPV16 infection(OR=1.95)and folic acid deficiency (OR=5.69).
2. Serum folic acid, FHIT gene CPG island methylation and cervical lesions
(1) Serum folic acid and FHIT gene CPG island hypermethylation
Rate of FHIT gene CPG island hypemethylation(31.7%) in low serum folic acid(<2.30ng/ml) is higher than that(2.2%) in high serum folic acid(≥2.31ng/ml),there is difference (χ2=29.22,P=0.000), the odds ratio is 20.47,95%CI:4.80-87.32.
(2) FHIT gene CPG island methylation and cervical lesions
Rate of FHIT gene CPG island methylation in LSIL(12.5%),HSIL(44.9%) and SCC(63.2%) is higher than the control(2.9%),the odds ratio is 5.0,8.52 and 60.00;95%CI is (1.14-22.00, 1.14-22.00 and 7.94-102.39).
(3) Serum folic acid and FHIT gene CPG island methylation were associated with cervical lesions
The results of Crossover analysis show that risk of serum folic acid deficiency and FHIT gene CPG island hypermethylation in SCC(OR=8.33) is higher than that when serum folic acid deficiency (OR=1.53)and FHIT gene CPG island hypermethylation(OR=1.39).
(4) HPV16 and FHIT gene CPG island hypermethylation were associated with cervical lesions
The results of Crossover analysis show that the risk of HPV16 infection and FHIT gene CPG island hypermethylation in SCC (OR=63.13) is higher than that when FHIT gene CPG island hypermethylation (OR=18.94) and HPV16 infection (OR=9.47).The risk of cervical lesions when FHITgene CPG island hpermethylation is higher than that HPV16 infection.
Conclusions
1. Serum folic acid deficiency and HPV16 infection was associated with the development of cervical lesions, they possibly have interaction in the development of cervical lesions.
2. Serum folic acid deficiency was related to FHIT gene CPG island hypermethylation,FHIT gene CPG island hypermethylation can increase the risk of cervical lesions.
3. Serum folic acid deficiency and FHITgene CPG island hypermethylation in cervical lesions may have interaction;HPV16 infection and FHIT gene CPG island hypermethylation in cervical lesions may have interaction.The risk of cervical lesions when FHIT gene CPG island hypermethylation may be higher than that HPV16 infection.
引文
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