食管癌肿瘤相关基因的遗传与表观遗传学研究
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摘要
[目的]分析环境、遗传及其交互效应在食管癌发生中的作用，探讨食管癌相关基因P16、MGMT和hMLH1启动子区DNA异常甲基化的分布规律及其与食管癌临床特征间的关系，并初步分析DNA异常甲基化与叶酸代谢酶基因MTHFR C677T多态间的联系。
[方法]选择上消化道癌高发区江苏省扬中市为研究现场，采用以人群为基础的病例对照研究设计，分析膳食、吸烟、饮酒、饮茶等环境因素与食管癌的关系。应用PCR和RFLP等分子生物学技术分析核苷酸切除修复基因XPC PAT和exon 15基因多态、叶酸代谢酶基因MTHFR C677T多态在食管癌发生中的作用及其与环境因素间的交互效应。食管癌病例从扬中市肿瘤登记报告系统获得，为2004年1月至2006年3月间新发的、经病理学明确诊断的食管鳞癌患者，要求年龄＞30岁，在扬中居住至少5年，并愿意参加调查者。在确诊后两周内进行流行病学问卷调查，收集空腹静脉血标本5ml。对照组选自同期居住在扬中境内的居民，与病例按性别和年龄组进行成组频数匹配，要求身体健康，无恶性肿瘤及胃和十二指肠溃疡病史，征得同意后采集静脉血并进行流行病学问卷调查。剪取手术患者的癌中心组织和边缘正常组织标本各二块，并收集10例正常健康成人食管粘膜标本。应用甲基化特异性PCR法检测癌组织、边缘组织和正常食管粘膜组织中肿瘤相关基因P16、MGMT和hMLH1启动子区甲基化状态，分析DNA异常甲基化是否与食管癌临床特征和环境因素间存在联系，并探讨食管癌相关基因异常甲基化与叶酸代谢酶基因MTHFR C677T多态间的关系。数据录入与分析分别采用EpiData和SPSS 11.0、STATA 9.2统计软件，应用单因素x~2检验和多因素非条件Logistic回归模型分析环境、遗传和表观遗传因素与食管癌的联系。
[结果]自2004年1月至2006年3月，共收集食管鳞状细胞癌病例355例，平均年龄61.5±7.9岁，男性62.8％，女性37.2％。对照408例，平均年龄60.8±8.3岁，男性61.8％，女性38.2％。按性别分层后发现一些不良膳食习惯如食物温度过高、喜食红烧肉、吃陈米等能增加食管癌患病危险，其中陈米摄入史的比值比OR在男女性中分别达到9.06(95％CI：5.93-13.84)和14.53(95％CI：7.82-27.02)。口味偏咸、喜辣食等仅在男性中观察到危险效应，OR分别为2.34(95％CI：1.57-3.48)和3.38(95％CI：2.12-5.39)。与不吸烟者相比，吸烟能增加男性食管癌患病危险，OR=1.98(95％CI：1.34—2.92)，随着吸烟年数和日吸烟支数增加，患病危险也随之增加。尽管在女性中未能观察到饮酒与食管癌间的联系具有统计学意义，但男性饮酒者患食管癌的危险增加，OR=2.20(95％CI：1.51-3.20)，随饮酒频率和饮酒年数增加，危险性也增加。与既往研究不同的是，本次研究仅观察到饮茶对女性食管癌有保护作用(OR=0.26，95％CI：0.07-0.94)。虽然食管癌患者的血清H．pyroli抗体阳性率低于对照组，但差异无统计学意义。
食管癌病例组和对照组中XPC PAT+等位基因频率分别是35.7％和37.1％，与野生基因型-／-比较，杂合子-／+和纯合变异型+／+的调整OR分别是0.80(95％CI：0.56-1.16)和1.04(95％CI：0.60-1.80)。病例组和对照组中XPC exon 15C等位基因频率分别是35.9％和37.2％，与野生基因型AA比较，杂合子AC和纯合变异型CC的调整OR分别0.79(95％CI：0.55-1.14)和1.03(95％CI：0.59-1.78)，未见XPCPAT和exon 15基因多态与食管癌遗传易感性间的联系具有统计学意义。
MTHFR 677T等位基因频率在食管癌病例组和对照组中分别为45.6％和45.3％，经性别、年龄、受教育年数、吸烟史、饮酒史、饮茶史和食用陈米史等变量调整后，CT、TT、CT／TT基因型的OR值分别是1.58(95％CI：1.06-2.36)、1.04(95％CI：0.64-1.68)和1.38(95％CI：0.96-2.01)。与野生型MTHFR 677CC基因型比较，携带杂合子CT基因型者患食管癌的危险增加，未见MTHFR C677T基因多态与环境因素间存在有统计学意义的交互效应。
对125例经病理学确诊的食管鳞癌手术标本分析，食管癌组织中P16基因甲基化频率较高，达88.0％，其次是MGMT基因27.2％，hMLH1基因启动子甲基化频率较低，仅3.2％，P16、MGMT和hMLH1任一基因呈现甲基化的频率是90.4％。食管癌手术切口边缘肉眼所见相对正常的食管粘膜组织中P16基因亦呈现较高的甲基化频率，达36.8％，其次是MGMT基因11.2％，无一例hMLH1基因呈现甲基化，P16、MGMT和hMLH1任一基因甲基化的频率是43.2％。10例正常健康对照的食管粘膜中相关基因启动子区均呈非甲基化状态。食管癌患者的区域淋巴结转移与否和DNA甲基化频率有关，存在淋巴结转移的患者癌组织中MGMT基因甲基化频率增高，达37.3％，远高于无淋巴结转移的患者(18.2％)。在手术切口边缘食管粘膜组织中，存在淋巴结转移的患者P16基因甲基化频率(49.2％)明显高于无淋巴结转移的患者(25.8％)。性别、年龄、烟酒史、癌肿部位、M分期等与DNA甲基化频率无关。MTHFRC677T基因多态可能与食管鳞癌组织中MGMT基因启动子甲基化程度有关，携带变异基因型者MGMT基因甲基化频率增加。
[结论]扬中市居民食管癌发生危险与不良膳食习惯、食用陈米、烟酒嗜好等因素有关，提倡健康的生活方式、戒烟、控酒是预防食管癌的重要措施之一。核苷酸切除修复基因XPC PAT和exon 15多态与食管癌遗传易感性间的联系较弱，叶酸代谢酶基因MTHFR C677T多态可能与食管癌遗传易感性和DNA异常甲基化有关。P16基因和MGMT基因启动子区异常甲基化与食管癌的发生和发展高度相关，探讨DNA异常甲基化的分布规律有望在食管癌早期诊断和预后监测方面发挥重要作用。
[Objective] This study aims to investigate the role of exogenous factors, genetic polymorphisms, aberrant CpG island methylation of P16、MGMT and hMLH1 genes and their relations in the risk of esophageal squamous cell carcinoma in a Chinese population.
[Methods]A population-based case-control study was conducted in Yangzhong County, Jiangsu Province of China, with histologically confirmed esophageal squamous cell carcinoma cases who were diagnosed between January 2004 and March 2006 while controls were selected from the local cancer-free individuals and group matched with cases by sex and age. Face-to-face interviews were conducted by the trained interviewers using a structured questionnaire and blood samples were collected with informed consent. For those patients having undergone surgery in the Yangzhong People's Hospital, tissues in the center of cancer focus and distant normal appearing esophagus were excised and stored in-70℃refrigerator. Ten histologically confirmed normal esophageal tissues from those who underwent gastroscopy examination were obtained in the Yangzhong People's Hospital. Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) methods were used to measure DNA damage repair gene XPC and folate metabolism enzyme gene MTHFR polymorphisms. Unconditional logistic regression model was used to measure the relationship between exogenous factors and genetic polymorphisms and the possible gene-environment interaction in the risk of esophageal cancer. Methylation Specific Polymerase Chain Reaction (MSP) was used to test the CpG island methylation status of cancer related genes P16, MGMT and hMLH1．The assocoation between methylation status of selected genes and clinical characteristics as well as the possible interaction between methyaltion status and MTHFR C677T polymorphisms were also analyzed.
[Results]Totally, 355 cases (men 62．8%, women 37．2%) were involved in this study with average age 61．5±7．9 years old, and group matched by 408 controls (men 61．8%, women 38．2%) with average age 60．8±8．3 years old. Stratified unconditional logistic regression analysis by sex showed that hot-temperature food items, pork braised in brown sauce and old stocked rice intake could increase the risk of esophageal cancer with odds ratio 2．13(95% confidence interval: 1．39-3．24)、2．06(95% confidence interval: 1．42-2．99) and 9．06(95% confidence interval:5．93-13．84) in men and with odds ratio 3．05(95% confidence interval: 1．73-5．36) , 1．91(95% confidence interval: 1．16-3．16) and 14．53(95% confidence interval:7．82-27．02) in women respectively. Diet high in salt and chili only showed risk effects in men with odds ratio 2．34(95% confidence interval: 1．57-3．48) and 3．38(95% confidence interval:2．12-5．39) respectively. Either tobacco smoking or alcohol drinking showed risk effects in the occurrence of esophageal cancer for men with odds ratio 1．98(95% confidence interval: 1．34-2．92) and 2．20(95% confidence interval:1．51-3．20) respectively. Green tea drinking seemed to be a protective factor for women with odds ratio 0．26(95% confidence interval:0．07-0．94) . The frequency of H.pylori lgG seropositive in esophageal cancer cases was 55．0% which was lower than that in controls (62．6%). However, the difference was not significant.
The frequency of allele XPC PAT+ and XPC exon 15C were 35．7% and 37．2% in cancer cases respectively. Compared with XPC PAT-/-genotype, the adjusted odds ratio for +/-and +/+ were 0．80(95% Cl:0．56-1．16) and 1．04(95% Cl:0．60-1．80) respectively. Compared with XPC exon 15 AA genotype, the adjusted odds ratio for AC and CC were 0．79(95% Cl:0．55-1．14) and 1．03(95% Cl:0．59-1．78) respectively. No significant relation was found between XPC polymorphisms and esophageal cancer.
The frequency of allele MTHFR 677T were 45．6% and 45．3% in cases and controls respectively. After adjusted by sex, age, education years, tobacco smoking, alcohol drinking, green tea drinking and old stocked rice intake, the odds ratio for MTHFR CT and TT were 1．58(95% Cl:1．06-2．36) and 1．04(95% Cl:0．64-1．68) when compared with MTHFR CC genotype. No interaction was found between MTHFR C677T genetic polymorphisms and selected environmental factors.
Aberrant CpG island hypermethylation of P16, MGMT and hMLH1 gene could be found in most cancer tissues with the frequency about 88．0%, 27．2% and 3．2% respectively, whereas the frequency of CpG island hypermethylation in any gene was 90．4%. Even in adjacent normal appearing esophageal tissues, the P16 and MGMT gene also showed high aberrant hypermethylation with the proportion at 36．8% and 11．2% respectively. Compared to those patients without lymph node metastasis, MGMT gene showed a higher proportion of hypermethylation in cancer tissues while P16 gene showed a higher proportion of hypermethylation in adjacent normal appearing esophageal tissues in patients with lymph node metastasis. A significant relation was found in this study between MTHFR C677T genetic polymorphisms and CpG island methylation status of MGMT gene in tumor tissues.
[Conclusions]Both exogenous factors and genetic factors might play important roles in the occurrence of esophageal squamous cell carcinoma. A healthy dietary habit, with smoking cessation and alcohol controlling is of a great importance in the prevention of esophageal cancer. MTHFR C677T genetic polymorphisms were associated with individual susceptibility to esophageal cancer and hypermethylation rate of MGMT gene in the tumor tissues. Aberrant CpG island hypermethylation of cancer related genes were strongly related with esophageal squmaous cell carcinoma and could be a promising biomarker in esophageal cancer diagnosis and prognosis.
[方法]选择上消化道癌高发区江苏省扬中市为研究现场，采用以人群为基础的病例对照研究设计，分析膳食、吸烟、饮酒、饮茶等环境因素与食管癌的关系。应用PCR和RFLP等分子生物学技术分析核苷酸切除修复基因XPC PAT和exon 15基因多态、叶酸代谢酶基因MTHFR C677T多态在食管癌发生中的作用及其与环境因素间的交互效应。食管癌病例从扬中市肿瘤登记报告系统获得，为2004年1月至2006年3月间新发的、经病理学明确诊断的食管鳞癌患者，要求年龄＞30岁，在扬中居住至少5年，并愿意参加调查者。在确诊后两周内进行流行病学问卷调查，收集空腹静脉血标本5ml。对照组选自同期居住在扬中境内的居民，与病例按性别和年龄组进行成组频数匹配，要求身体健康，无恶性肿瘤及胃和十二指肠溃疡病史，征得同意后采集静脉血并进行流行病学问卷调查。剪取手术患者的癌中心组织和边缘正常组织标本各二块，并收集10例正常健康成人食管粘膜标本。应用甲基化特异性PCR法检测癌组织、边缘组织和正常食管粘膜组织中肿瘤相关基因P16、MGMT和hMLH1启动子区甲基化状态，分析DNA异常甲基化是否与食管癌临床特征和环境因素间存在联系，并探讨食管癌相关基因异常甲基化与叶酸代谢酶基因MTHFR C677T多态间的关系。数据录入与分析分别采用EpiData和SPSS 11.0、STATA 9.2统计软件，应用单因素x~2检验和多因素非条件Logistic回归模型分析环境、遗传和表观遗传因素与食管癌的联系。
[结果]自2004年1月至2006年3月，共收集食管鳞状细胞癌病例355例，平均年龄61.5±7.9岁，男性62.8％，女性37.2％。对照408例，平均年龄60.8±8.3岁，男性61.8％，女性38.2％。按性别分层后发现一些不良膳食习惯如食物温度过高、喜食红烧肉、吃陈米等能增加食管癌患病危险，其中陈米摄入史的比值比OR在男女性中分别达到9.06(95％CI：5.93-13.84)和14.53(95％CI：7.82-27.02)。口味偏咸、喜辣食等仅在男性中观察到危险效应，OR分别为2.34(95％CI：1.57-3.48)和3.38(95％CI：2.12-5.39)。与不吸烟者相比，吸烟能增加男性食管癌患病危险，OR=1.98(95％CI：1.34—2.92)，随着吸烟年数和日吸烟支数增加，患病危险也随之增加。尽管在女性中未能观察到饮酒与食管癌间的联系具有统计学意义，但男性饮酒者患食管癌的危险增加，OR=2.20(95％CI：1.51-3.20)，随饮酒频率和饮酒年数增加，危险性也增加。与既往研究不同的是，本次研究仅观察到饮茶对女性食管癌有保护作用(OR=0.26，95％CI：0.07-0.94)。虽然食管癌患者的血清H．pyroli抗体阳性率低于对照组，但差异无统计学意义。
食管癌病例组和对照组中XPC PAT+等位基因频率分别是35.7％和37.1％，与野生基因型-／-比较，杂合子-／+和纯合变异型+／+的调整OR分别是0.80(95％CI：0.56-1.16)和1.04(95％CI：0.60-1.80)。病例组和对照组中XPC exon 15C等位基因频率分别是35.9％和37.2％，与野生基因型AA比较，杂合子AC和纯合变异型CC的调整OR分别0.79(95％CI：0.55-1.14)和1.03(95％CI：0.59-1.78)，未见XPCPAT和exon 15基因多态与食管癌遗传易感性间的联系具有统计学意义。
MTHFR 677T等位基因频率在食管癌病例组和对照组中分别为45.6％和45.3％，经性别、年龄、受教育年数、吸烟史、饮酒史、饮茶史和食用陈米史等变量调整后，CT、TT、CT／TT基因型的OR值分别是1.58(95％CI：1.06-2.36)、1.04(95％CI：0.64-1.68)和1.38(95％CI：0.96-2.01)。与野生型MTHFR 677CC基因型比较，携带杂合子CT基因型者患食管癌的危险增加，未见MTHFR C677T基因多态与环境因素间存在有统计学意义的交互效应。
对125例经病理学确诊的食管鳞癌手术标本分析，食管癌组织中P16基因甲基化频率较高，达88.0％，其次是MGMT基因27.2％，hMLH1基因启动子甲基化频率较低，仅3.2％，P16、MGMT和hMLH1任一基因呈现甲基化的频率是90.4％。食管癌手术切口边缘肉眼所见相对正常的食管粘膜组织中P16基因亦呈现较高的甲基化频率，达36.8％，其次是MGMT基因11.2％，无一例hMLH1基因呈现甲基化，P16、MGMT和hMLH1任一基因甲基化的频率是43.2％。10例正常健康对照的食管粘膜中相关基因启动子区均呈非甲基化状态。食管癌患者的区域淋巴结转移与否和DNA甲基化频率有关，存在淋巴结转移的患者癌组织中MGMT基因甲基化频率增高，达37.3％，远高于无淋巴结转移的患者(18.2％)。在手术切口边缘食管粘膜组织中，存在淋巴结转移的患者P16基因甲基化频率(49.2％)明显高于无淋巴结转移的患者(25.8％)。性别、年龄、烟酒史、癌肿部位、M分期等与DNA甲基化频率无关。MTHFRC677T基因多态可能与食管鳞癌组织中MGMT基因启动子甲基化程度有关，携带变异基因型者MGMT基因甲基化频率增加。
[结论]扬中市居民食管癌发生危险与不良膳食习惯、食用陈米、烟酒嗜好等因素有关，提倡健康的生活方式、戒烟、控酒是预防食管癌的重要措施之一。核苷酸切除修复基因XPC PAT和exon 15多态与食管癌遗传易感性间的联系较弱，叶酸代谢酶基因MTHFR C677T多态可能与食管癌遗传易感性和DNA异常甲基化有关。P16基因和MGMT基因启动子区异常甲基化与食管癌的发生和发展高度相关，探讨DNA异常甲基化的分布规律有望在食管癌早期诊断和预后监测方面发挥重要作用。
[Objective] This study aims to investigate the role of exogenous factors, genetic polymorphisms, aberrant CpG island methylation of P16、MGMT and hMLH1 genes and their relations in the risk of esophageal squamous cell carcinoma in a Chinese population.
[Methods]A population-based case-control study was conducted in Yangzhong County, Jiangsu Province of China, with histologically confirmed esophageal squamous cell carcinoma cases who were diagnosed between January 2004 and March 2006 while controls were selected from the local cancer-free individuals and group matched with cases by sex and age. Face-to-face interviews were conducted by the trained interviewers using a structured questionnaire and blood samples were collected with informed consent. For those patients having undergone surgery in the Yangzhong People's Hospital, tissues in the center of cancer focus and distant normal appearing esophagus were excised and stored in-70℃refrigerator. Ten histologically confirmed normal esophageal tissues from those who underwent gastroscopy examination were obtained in the Yangzhong People's Hospital. Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) methods were used to measure DNA damage repair gene XPC and folate metabolism enzyme gene MTHFR polymorphisms. Unconditional logistic regression model was used to measure the relationship between exogenous factors and genetic polymorphisms and the possible gene-environment interaction in the risk of esophageal cancer. Methylation Specific Polymerase Chain Reaction (MSP) was used to test the CpG island methylation status of cancer related genes P16, MGMT and hMLH1．The assocoation between methylation status of selected genes and clinical characteristics as well as the possible interaction between methyaltion status and MTHFR C677T polymorphisms were also analyzed.
[Results]Totally, 355 cases (men 62．8%, women 37．2%) were involved in this study with average age 61．5±7．9 years old, and group matched by 408 controls (men 61．8%, women 38．2%) with average age 60．8±8．3 years old. Stratified unconditional logistic regression analysis by sex showed that hot-temperature food items, pork braised in brown sauce and old stocked rice intake could increase the risk of esophageal cancer with odds ratio 2．13(95% confidence interval: 1．39-3．24)、2．06(95% confidence interval: 1．42-2．99) and 9．06(95% confidence interval:5．93-13．84) in men and with odds ratio 3．05(95% confidence interval: 1．73-5．36) , 1．91(95% confidence interval: 1．16-3．16) and 14．53(95% confidence interval:7．82-27．02) in women respectively. Diet high in salt and chili only showed risk effects in men with odds ratio 2．34(95% confidence interval: 1．57-3．48) and 3．38(95% confidence interval:2．12-5．39) respectively. Either tobacco smoking or alcohol drinking showed risk effects in the occurrence of esophageal cancer for men with odds ratio 1．98(95% confidence interval: 1．34-2．92) and 2．20(95% confidence interval:1．51-3．20) respectively. Green tea drinking seemed to be a protective factor for women with odds ratio 0．26(95% confidence interval:0．07-0．94) . The frequency of H.pylori lgG seropositive in esophageal cancer cases was 55．0% which was lower than that in controls (62．6%). However, the difference was not significant.
The frequency of allele XPC PAT+ and XPC exon 15C were 35．7% and 37．2% in cancer cases respectively. Compared with XPC PAT-/-genotype, the adjusted odds ratio for +/-and +/+ were 0．80(95% Cl:0．56-1．16) and 1．04(95% Cl:0．60-1．80) respectively. Compared with XPC exon 15 AA genotype, the adjusted odds ratio for AC and CC were 0．79(95% Cl:0．55-1．14) and 1．03(95% Cl:0．59-1．78) respectively. No significant relation was found between XPC polymorphisms and esophageal cancer.
The frequency of allele MTHFR 677T were 45．6% and 45．3% in cases and controls respectively. After adjusted by sex, age, education years, tobacco smoking, alcohol drinking, green tea drinking and old stocked rice intake, the odds ratio for MTHFR CT and TT were 1．58(95% Cl:1．06-2．36) and 1．04(95% Cl:0．64-1．68) when compared with MTHFR CC genotype. No interaction was found between MTHFR C677T genetic polymorphisms and selected environmental factors.
Aberrant CpG island hypermethylation of P16, MGMT and hMLH1 gene could be found in most cancer tissues with the frequency about 88．0%, 27．2% and 3．2% respectively, whereas the frequency of CpG island hypermethylation in any gene was 90．4%. Even in adjacent normal appearing esophageal tissues, the P16 and MGMT gene also showed high aberrant hypermethylation with the proportion at 36．8% and 11．2% respectively. Compared to those patients without lymph node metastasis, MGMT gene showed a higher proportion of hypermethylation in cancer tissues while P16 gene showed a higher proportion of hypermethylation in adjacent normal appearing esophageal tissues in patients with lymph node metastasis. A significant relation was found in this study between MTHFR C677T genetic polymorphisms and CpG island methylation status of MGMT gene in tumor tissues.
[Conclusions]Both exogenous factors and genetic factors might play important roles in the occurrence of esophageal squamous cell carcinoma. A healthy dietary habit, with smoking cessation and alcohol controlling is of a great importance in the prevention of esophageal cancer. MTHFR C677T genetic polymorphisms were associated with individual susceptibility to esophageal cancer and hypermethylation rate of MGMT gene in the tumor tissues. Aberrant CpG island hypermethylation of cancer related genes were strongly related with esophageal squmaous cell carcinoma and could be a promising biomarker in esophageal cancer diagnosis and prognosis.
引文
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