肥城市食管鳞癌不同衍变阶段的影响因素研究
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摘要
研究背景
食管癌是世界上最常见的六大恶性肿瘤之一，我国每年约有25万新诊断的病例，占全世界病例数的一半。在河南、山西、河北三省交界的太行山南侧地区，其发病率高达100／10万以上。河南省林州市(原林县)和河北省磁县是我国、也是世界上食管癌发病率和死亡率最高的地区。此外，我国其他地区，如福建省安溪县、广东省南澳县、江苏省淮安市、四川省盐亭县、山东省肥城市等的食管癌发病率也较高。
食管上皮癌变是一个多阶段、进行性衍变的过程，正常食管上皮由于某种原因的刺激产生炎症，然后到炎性增生，再发展为不典型增生，进一步发展为癌。食管癌前病变突出的临床特征是其双向发展不稳定特性，即其可向癌的方向持续发展，也可以停留在某一阶段多年不变，甚至可以退回到正常状态。
从20世纪70年代以来，在食管癌高发区进行普查发现，其他食管疾病的患病率也非常高。如1983年在河南省林县由12649人参加的食管脱落细胞学拉网检查发现，基底细胞增生、轻度不典型增生、中度不典型增生、近癌及食管癌的检出率分别为38％、21％、6％、2％、2％。其他食管疾病与食管癌有相同的影响因素，如男性慢性食管炎的检出率高于女性，有食管癌家族史者慢性食管炎检出率明显高于无食管癌家族史者。另外，轻度增生、重度增生和食管癌的平均患病年龄依次增高，表明食管增生是食管癌的必经阶段。
对不同地区、不同时间进行的比较研究发现，食管癌及其衍变的各个阶段的检出率有一致的表现。食管癌高发区食管炎症、基底细胞增生及不典型增生的检出率高于低发区。1980年和2004年对河南省林州市同一地区居民进行的食管内镜与组织学检查发现，两次食管癌检出率无统计学差异，而非典型性增生表现出相同的结果，也未发现有统计学差异。
在高发区进行的前瞻性研究发现，食管炎症、增生与食管癌具有明显的联系。在河南省高发区进行的30—78个月随访研究发现，单纯炎症或增生患者的食管癌发病率为4.03％，而不典型增生患者的发病率高达33.87％。另一项15年的随访研究发现，正常食管黏膜、轻度不典型增生、中度不典型增生、重度不典型增生发展为食管癌的率依次增高，分别为2.4％、5.0％、8.3％、10.3％。
对食管癌手术标本的观察发现，从癌旁组织中可以看到，单纯性增生、不典型增生到原位癌的发展过程，而且癌旁组织的种类与食管癌的分化程度有关。对大白鼠、犬等实验动物给予致癌物质，也观察到了食管先后经过基底细胞增生、不典型增生，然后发展为癌的过程。在河南省林县进行的一项干预研究中，食管重度增生患者服用核黄素，取得了较好的远期效果，试验组的的癌变率低于对照组，差异有统计学意义，说明对食管不同衍变阶段的干预治疗，是预防食管癌发病的一条有效途径。总之，有明显的证据表明，食管癌的发展是一个多阶段的过程，研究其衍变的规律及各阶段的影响因素，对预防食管癌的发生具有重要的理论和实践意义。
传统流行病学对食管癌的流行病学特征及影响因素研究发现，食管癌的发病与性别、年龄有关，且存在明显的地理分布特点：农村高于城市、山区高于平原。其影响因素包括生活习惯(如吸烟、饮酒)、肿瘤家族史、饮食结构等。但传统流行病学难以对高危险性个体中仅仅很少的人会发病做出解释。随着基因学的发展，人们开始认识到这种现象可能与基因遗传易感性不同有关。从代谢酶基因、DNA修复基因、抑癌基因和癌基因突变研究与食管癌发生的关联，已成为分子流行病学研究重点之一。
促血管生成素2(angiopoietin 2，Ang2)是较受关注的广谱肿瘤标志物，对临床手术标本研究发现，Ang2在食管癌中的表达高于癌旁及周围对照组织，但未见随着食管癌前病变等级增加患者血清Ang2水平是否升高的报道。
目前已经报道的食管癌影响因素主要来自病例对照研究，病例为食管癌患者，对照多为一般人群或医院非癌患者，而选择的对照往往没有经过食管黏膜是否正常的检查，难免产生由对照选择引入的偏倚。对食管非恶性疾病及食管癌前病变的影响因素的研究鲜有报道，更没有见到在高发社区同时进行多阶段食管癌前疾病和食管癌的病例对照研究。因此，有必要对同一群体不同食管疾病的危险因素进行研究，为食管癌的一级预防和二级预防提供理论依据；同时也有利于发现与食管癌变阶段有关联的生物标志物，以便为危险个体的动态监测提供评价指标。
20世纪70年代到90年代，山东省进行过3次恶性肿瘤回顾调查，资料分析显示，食管癌的高发区局限在肥城市和宁阳县，其周围县市为偏高区。全省1990—1992年恶性肿瘤死因排序表明，食管癌死亡率为18.22／10万人口，居第4位，占所有恶性肿瘤死亡的15.44％。1970—1974、1985—1989、1990—1992、1997—1999年4个时期肥城市食管癌死亡率分别为63.19／10万(以下略去／10万)、71.68、66.87和82.33；标化死亡率(以1964年中国人口标化)分别为45.37、46.67、51.21、46.32，呈平稳状态。男女比例为2：1。2000—2004年死亡率为71.07，标化死亡率为34.64。从标化率的变化看，近年来有下降的趋向。
肥城市食管癌尚未进行病因干预，多年来仅进行了死亡监测和高低发区对比研究。1999年建立了肿瘤发病死亡登记报告制度；2003年被列为山东省可持续发展十大科技示范工程之一，在该地开展食管癌的早期筛查防治研究。
研究目的
首先采用传统流行病学和分子流行病学方法，分析食管癌前不同疾病阶段的影响因素；然后采用基因-环境设计，研究乙醛脱氢酶2(aldehyde dehydrogenase 2，ALDH2)基因、维生素D基因受体(vitamin D receptor，VDR)基因的多态性与食管癌前不同疾病的关联；并对可能与癌衍变阶段有关联的生物标志物sAng2的水平进行了检测；以便为预防食管疾病的发生，制订降低高危人群食管癌发病率的措施提供理论依据。
研究方法
1食管癌不同衍变阶段的定义本研究所指的食管癌均为食管鳞癌，将其不同衍变阶段定义为：食管黏膜上皮正常—食管炎—基底细胞增生—不典型增生(轻度、中度、重度)—早期癌(含原位癌)—晚期癌。
2食管癌不同衍变阶段的影响因素2004年10月—2005年10月，对肥城市—乡镇40—69岁人群作免费内镜普查。内容包括(1)问卷调查：包括性别、年龄、文化程度、婚姻状况、职业、家庭人年均收入等一般情况；肿瘤家族史(胃癌、食管癌、其他肿瘤)；行为习惯(吸烟、饮酒等)；饮食情况(主副食、蔬菜、水果)；(2)采集空腹外周血5ml，按RT-PCR方法要求分离和保存血清和血粒细胞；(3)消化内镜(电子内镜)检查，对未染色部分取活检组织作病理学检查，结果分为正常、炎症、基底细胞增生、轻度不典型增生、中度不典型增生、重度不典型增生、原位癌、早期癌。将早期癌、增生、炎症患者分别作为指示病例组，癌组由普查发现病例和住院病例两部分组成，内镜检查正常食管黏膜为指示对照组。描述各种食管疾病的流行病学特征，分析吸烟、饮酒、肿瘤家族史、饮食及其营养成分在不同食管病变的频数分布与作用。
3 ALDH2基因、VDR基因与食管癌不同衍变阶段易感性的关联从食管癌、不典型增生、基底细胞增生、炎症、正常者中抽取部分样本，提取DNA，检测与酒精代谢有关的ALDH2基因、与营养素代谢有关的VDR基因的多态性。另外，还分析了2种基因与吸烟、饮酒相结合对食管疾病的影响。
4 sAng2与食管癌衍变阶段的关联选取正常人、炎症、增生、早期食管鳞癌和晚期食管鳞癌患者血清共261份，进行Ang2测定，分析其与癌变各阶段的关联。
5统计学处理定性指标采用相对数比较，显著性检验用x~2检验。采用多项式Logistic回归分析危险因素，观察指标为比值比(OR)及其95％可信区间(95％CI)。以(?)±s表示sAng2水平，采用方差分析比较各组差别，采用等级相关分析其与癌变阶段的相关性。
数据录入及分析利用SPSS12.0软件完成。
主要研究结果
1共3253人参加内镜普查，其中5例资料不全未用于分析。从中发现食管早期癌20例、增生266例、炎症144例和食管黏膜正常2818例。鉴于早期癌病例较少，为了增加样本量，加入了在肥城市人民医院接受住院治疗的51例食管癌患者的资料，与普查得到的早期癌病例合为癌组分析。性别、年龄、文化水平、人年均收入在各组人群间存在统计学差异，婚姻状况、职业无统计学差异。
2吸烟与不吸烟比较，OR在食管癌组最高，但未达到显著性水平。按吸烟指数分析，吸烟指数＞500在食管癌组和增生组的OR分别为2.3(95％CI：1.10—4.86)和1.5(95％CI：1.01—2.18)，均达到显著性水平。
3饮酒与不饮酒比较，饮酒在食管癌、炎症组OR分别为2.8(95％CI：1.35—5.76)和1.8(95％CI：1.08—5.87)，达到显著性水平。按饮酒指数分析，在饮酒指数＞30和≤30两个水平上，均与食管癌组有关联，OR分别为3.1(95％CI：1.35—5.76)和2.5(95％CI：1.12—5.69)，并显示出“剂量-效应”趋向。饮酒指数≤30在炎症组OR也达到显著性水平。
4将吸烟和饮酒结合分析，以不吸烟+不饮酒为比较的基线水平(OR=1.0)，吸烟+饮酒与食管癌有显著性关联，OR为2.8(95％CI：1.18—6.64)。
5将对照组吸烟和饮酒暴露率作为人群中暴露的参数，吸烟+饮酒在食管癌、增生、炎症的人群归因危险百分比(PARP)分别为36.8％、11.5％、26.3％。
6有食管癌家族史在食管癌、增生、炎症组的OR分别为2.0(95％CI：1.09—3.60)、1.8(95％CI：1.27—2.45)、1.8(95％CI：1.17—2.72)；按亲缘系数分析，一级血亲患食管癌在3组的OR分别为2.6(95％CI：1.36—4.85)、2.1(95％CI：1.43—2.99)、1.8(95％CI：1.13—3.03)。
7将食管癌家族史与吸烟结合分析，单独有食管癌家族史与食管癌无显著性关联，而有食管癌家族史+吸烟的OR为3.3(95％CI：1.33—8.31)。
8将食管癌家族史及饮酒结合分析，仅有食管癌家族史在食管癌、增生、炎症组的OR均未达到显著性水平，但合并饮酒后均达到显著性水平，且明显升高，OR分别为5.8(95％CI：1.40—3.77)、2.3(95％CI：2.21—15.04)、3.3(95％CI：1.73—6.33)。
9肉类是食管癌的危险因素，大豆、鱼类、油类、芹菜、茄子、芸豆、青椒、脂肪、粗纤维素、灰分、钙能降低其危险性；小麦、油类、热量是食管增生的危险因素，韭菜具有预防作用；油类、热量是食管炎症的危险因素。
10分析ALDH2与不同食管疾病的关联，以A／A型基因作为比较的基线，G／G型OR在不典型增生、基底细胞增生组达到显著性水平，其中在基底细胞增生组最高，为6.6(95％CI：2.19—20.07)。以不吸烟+A／A作为比较的基线(OR=1.0)，发现G基因型与吸烟结合增加癌和不典型增生组的危险性，其中癌组ALDH2 G／A型OR为12.7(95％CI：1.62-100.70)，有发现G基因型与吸烟结合增加食管炎症或基底细胞增生的危险性。将基因型与饮酒结合分析，以不饮酒+A／A作为比较的基线(OR=1.0)，饮酒+G／G在不典型增生组和基底细胞增生组达到显著性水平，OR分别为2.8(95％CI：1.02—7.86)和16.1(95％CI：2.01—129.39)。
11分析VDR基因型与食管疾病的关系，与T／t比较，T／T的OR在食管癌、不典型增生、基底细胞增生和炎症组均未达到显著性水平，也未发现VDR基因型与吸烟、饮酒的交互作用。
12按sAng2试剂盒说明书规定，正常、炎症、增生、早期癌、中晚期癌高出正常值的比例分别为7.7％、6.8％、2.4％、23.1％、78.6％。相关分析显示，sAng2与癌变过程指示变量的等级相关系数为0.206，P＜0.01(双尾)，二者存在正相关，有统计学意义；但属于低度相关，表明sAng2随着疾病向癌变等级增加血清中的表达水平增高。
结论
1传统流行病学分析发现食管非恶性疾病、癌前病变和癌的危险因素有差异，分别是：(1)癌：吸烟、饮酒、食管癌家族史；(2)增生：吸烟、食管癌家族史；(3)炎症：饮酒、食管癌家族史。饮食及其营养成分与各种食管疾病均有关联。在各不同疾病阶段都存在吸烟、饮酒及食管癌家族史三者之间的交互作用。
2基因-环境分析发现食管非恶性疾病、癌前病变和癌的危险因素也有差异。ALDH2 G／G型与癌前不典型增生、基底细胞增生有关联，G基因型与吸烟结合增加癌和不典型增生组的危险性。ALDH2 G／G型及饮酒在食管各不同疾病阶段中都有交互作用。没有发现VDR基因与食管各阶段疾病有关联。
3传统流行病学分析表明，各种危险因素在癌组的OR大于炎症组及增生组；而ALDH2基因与环境因素的研究表明，各种危险因素对食管增生的影响较为明显。
4 sAng2水平与食管黏膜上皮癌前病变程度有一定关联，可能对高危险个体长期监测有一定意义。
意义与创新
1本研究选取一食管癌高发乡镇进行碘染色内镜检查，对照组与病例组来自同一人群，他们拥有相同或相似的生活环境、风俗习惯，具有较好的可比性。病例及对照均经染色内镜或／和组织病理学确诊，误分类的可能性极小，且为新发病例，提供的信息一般不存在回忆偏倚，生活尚未因发病而改变。因此，本研究结果可靠。
2按照食管鳞癌衍变的不同阶段疾病，采用多序列病例-对照研究分析和分子流行病学基因遗传多态性与环境因素分析各个阶段发生的危险因素，将传统流行病学与分子流行病学结合起来观察食管癌不同衍变阶段的影响因素，不仅对理解食管癌发生过程有病理生理性学术意义，可为高发区疾病预防提供新的流行病学研究途径，更重要的是可以为癌前疾病阶段开展防治提供科学依据。
国内外目前尚未见在高发区同时对食管癌衍变不同阶段危险因素进行研究的报道。
不足与建议
不足：
1检出的食管癌不同衍变阶段疾病的样本数尚不足够大，本研究的发现有待进一步增大样本量进行考察。
2检测2种基因型时，测定的样本例数不完全一致，没有进行2种基因的交互作用分析。
建议：
对检出的各个阶段非恶性疾病进行动态监测，观察食管癌不同衍变阶段的发展变化，并能进行干预性研究以及观测某些生物标志物的变化，为建立高危险人群动态监测及癌的早期筛查指标提供契机。
Esophageal squamous cell carcinoma (ESCC) is one of the most common carcinomas in the world. There are about 250 000 newly diagnosed patients with ESCC every year, ranking the 4th in carcinomas in China. Most areas have a low prevalence in China, but the south area of the Taihang Mountain, which is the boundary of He'nan, Shanxi, and Hebei has a high prevalence of 100/100 000. Linzhou City (originally named as Lin County) and Ci County have the highest prevalence and mortality of ESCC in China, as well as in the world. Furthermore, several other areas in China, such as Anxi County in Fujian Province, Nan'ao County in Guangdong Povince, Huai'an City in Jiangsu Province, Yanting County in Sichuan Province and Feicheng City in Shandong Province have high prevalence of ESCC too.
The clinical characteristics of precancerous esophageal leasions are bidirectional and inconstant. In other words, the lesions may either develop into a carcinoma or stay in a certain stage for quite many years, even turn to normal status.
Some investigations ever since 1970s have revealed the fact that the prevalence of other esophageal diseases is also higher in areas with high prevalence of ESCC than in other areas.
An esophageal balloon-cytology screening was carried out in Lin County. Among the 12649 participants 38% showed hyperplasia, 21% showed atypical hyperplasia 1, 6% showed atypical hyperplasia 2, 2% showed near-carcinoma and 2% showed carcinoma. ESCC and other esophageal diseases have common risk factors. For instance, the prevalence rate of ESCC is higher in males than in females, and the prevalence rate of chronic esophageal inflammation is higher in males too; the prevalence rate is high in those who have an ESCC family history. The age of patients with gentle atypical hyperplasia, severe atypical hyperplasia and carcinoma gradually increased, indicating esophageal atypical hyperplasia is a transitional stage of ESCC.
Many comparative studies between different areas or periods showed that the prevalence of ESCC is accordant with the prevalence of non-malignant esophageal diseases. The prevalence of esophageal inflammation, base cell hyperplasia and atypical hyperplasia is higher in areas with a high carcinoma rate than in areas with a low carcinoma rate. Two studies carried out in Linzhou City in 1980 and 2004 respectively found that there was no significant difference in ESCC prevalence, and that there was no significant difference in atypical hyperplasia prevalence too.
Prospective studies in areas with high ESCC rate demonstrated the significant correlation between esophagitis, base hyperplasia and ESCC. A follow-up study of 30-78 months in the high incidence area of He'nan Province showed that 4.03% of the patients with esophagitis or simple hyperplasia and 33.87% of the patients with atypical hyperplasia developed ESCC. Another 15-year-follow- up revealed that the incidence rate of normal esophageal mucosa, gentle atypical hyperplasia, moderate atypical hyperplasia and severe atypical hyperplasia to ESCC are as follows, 2.4%, 5.0%, 8.3% and 10.3%, respectively.
Through the observation on surgery specimens the developing process of ESCC can be found from simple hyperplasia to atypical hyperplasia and carcinoma in situ, and the features of surrounding tissues are related to the differentiation of ESCC. Many experimental studies on animals such as rats or dogs also demonstrated this process. One intervention study in Lin County showed that patients with severe hyperplasia subjected to drug interruption had a lower prevalence of ESCC than the control group, suggesting that intervention therapy on non-malignant esophageal lesions is effective to prevent ESCC. Obviously, it is important to study the development and risk factors of non-malignant lesions to decrease the prevalence and mortality of ESCC.
ESCC is related with age and sex and geographical environment, with a higher incidence in countryside than cities and a higher incidence in mountain area than in champaign. Its influencing factors include life habits (such as smoking and drinking), carcinoma family history, and diet etc. It is difficult to calculate the disease probability to an individual only using traditional epidemiology. For example, among the people who smoke, drink and have a family history of ESCC, only a few develop ESCC. This phenomenon is caused by different hereditary susceptibilities, so it is necessary to study the influencing factors on the level of molecular biology.
Studies on surgery specimens showed that angiopoietin-2 (Ang2) is highly expressed in many carcinoma tissues. It has been reported that Ang2 is higher in ESCC tissues than in surrounding and normal tissues, but no information about the Ang2 level is reported in the serum of different esophagus diseases.
Studies on influencing factors of ESCC mostly adopt case-control designs, in which the experiment group consisted of pathologically diagnosed patients and the control group consisted of healthy people or non-carcinoma inpatients. Selection bias was inevitable in these studies because the esophagus mucosa of the controls were not examined. The influencing factors of non-malignant esophageal lesions were seldom studied, and no multi-stage case-control study in a high incidence community was reported on precarcinomaous diseases and ESCC.
From 1970s to 1990s, malignant neoplasms investigations in Shandong Province were carried out for three times. The results showed that the prevalence rate of ESCC was high in Feicheng City and Ningyang County, relatively high in their surrounding areas and low in the east. A study in 1990-1992 showed that ESCC in Shandong Province accounted for 15.44% and ranked the 4~(th) in all carcinomas, with a mortality of 18.22/100000. The retrospective analysis showed that the mortality of ESCC in Feicheng City in 1970-1974, 1985-1989, 1990-1992, and 1997-1999 was 63.19, 71.68, 66.87 and 82.33/100,000 respectively, and the standard mortality (standardized by the population data of 1964 in China) was 45.37, 46.67, 51.21, 46.32/100000 respectively. The ratio of male to female was 2: 1. The mortality of ESCC was 71.07/100000 and the standard mortality was 34.64/100,000 in the period of 2000-2004, showing a declining incidence in recent years.
The death surveillance and comparative study with low prevalence areas have been carried out but no intervention has been given in Feicheng City. In 1999 the report system on carcinoma occurrences and deaths was established, and in 2003 it was authorized as one of the ten sustainable development model areas for the early screening and prevention of ESCC.
Objective
The purpose of the present study was to provide theoretical bases and suggestions to decline the ESCC incidence in people with high risk. The epidemiological characteristics and influencing factors of ESCC and other esophageal lesions were analyzed; the associations of aldehyde dehydrogenase-2 (ALDH2) and vitamin D receptor (VDR) genes with ESCC and other esophageal diseases were studied by a gene-environment design; and the level of angiopoietin-2 were detected in normal controls and patients with different esophageal lesions to calculate its possibility as a biomolecular marker.
Methods
1 Definition of different stages of ESCC
In the present study the esophageal carcinoma was referred as ESCC and its development process were divide into the following stages: normal mucosa, esophagitis, basal cell hyperplasia, displasia (mild, moderate, and severe), early carcinoma (including carcinoma in situ), and advanced carcinoma.
2 Risk factors for different stages of ESCC
From Oct. 2004 to Oct. 2005, the residents of 40-69 years old in a town of Feicheng City participated in a free screening program. Investigation contents were as follows: (1) Questionnaire investigation included general information, such as sex, age, .culture, marriage condition, profession, family average income; family history of gastric, esophageal and other carcinomas; life habits, such as smoking and drinking habits; and diet, such as staple food, non-staple food, vegetables, fruit and their nutrient elements. (2) 5 ml venous blood was collected at 9-10 am after a 12-h fast from each participant. The sample was centrifuged for 10 min at 3000 r/min to separate plasma and obtain blood cells. (3) I-staining esophageal endoscope examination was made by seasoned endoscope doctors. Subjects with normal esophageal mucosa consisted of control group and those whose esophageal tract was not I-stained were pathologically examined. The pathological results were classified into seven categories: esophagitis, basal cell hyperplasia, mild atypical hyperplasia, moderate atypical hyperplasia, severe atypical hyperplasia, carcinoma in situ, and early carcinoma. Cases of carcinoma (including some ESCC patients accepting surgery in Peoples' Hospital of Feicheng City), hyperplasia and esophagitis were selected as index groups respectively, and subjects with normal esophageal mucosa were selected as control group. The epidemiological features of esophageal diseases and the frequency distribution of possible influencing factors were analyzed and described.
3 Effect of ALDH2 and VDR genes on different stages of ESCC
Based on the results of esophageal endoscope and pathological examination, subjects were classified into 5 groups: ESCC, atypical hyperplasia, basal cell hyperplasia, esophagitis and normal. DNA of some samples was genotyped for ALDH2 and VDR polymorphisms. Reasons for choosing these two genes were that they are respectively associated with the alcohol metabolism and nutrition deficiency, which were found as two possible risk factors of ESCC in our former studies. In addition, given that smoking and drinking may be associated with esophageal diseases, the effect of the two genes combined with smoking and drinking was also analyzed.
4 Association of serum Ang-2 level with the process of ESCC
Serum Ang-2 of 261 normal subjects, patients with esophagitis, hyperplasia, early carcinoma and advanced carcinoma was tested to analyzed.
5 Statistical analysis
Qualitative data were compared by relative ratio and chi-square test was used to evaluate differences in the frequency distributions of various potential risk factors among different stages of ESCC. Polynomial Logistic regression was used to analyze risk factors. The observation indexes were odds ratios (ORs) and 95% confidence intervals (95%C/s). The serum angiopoietin-2 level was described as (x|-)±s. ANOVA was used to compare the differences among different groups. The association of serum Ang-2 with the process of ESCC were calculated with rank correlation .
All data were input and analyzed by SPSS 12.0.
Results
1 A total of 3253 subjects participated in the enscope screening. Data from 5 cases were incomplete and were excluded. The examination result was as follows: early carcinoma, 20; hyperplasia, 266; esophagitis, 144; and normal mucosa, 2818. In addition, we selected 51 inpatients with ESCC, so the carcinoma group included 71 patients. There were significant differences among different groups in terms of sex, age, culture and family average income. However, there were no differences in terms of marriage or occupation.
2 After adjustment of sex, age, culture, and family average income, the OR ofsmoking to nonsmoking was the highest in ESCC group but had no statisticalsignificance. The OR of smoking index >500 was 2.3 (95%CI: 1.10-4.86) and 1.5(95%CI: 1.01-2.18) in ESCC group and hyperplasia group respectively, which reached the significant level.
3 The OR of drinking to nondrinking in ESCC group and hyperplasia group was 2.8 (95%CI: 1.35-5.76) and 1.8 (95%CI: 1.08-5.87) respectively, which reached the significant level. According to drinking index, drinking was associated with ESCC in >30 and <30 levels, with ORs of 3.1 (95%CI: 1.35-5.76) and 2.5(95%CI: 1.12-5.69) respectively. In addition, OR of drinking index <30 reached significant level in esophagitis group.
4 If nonsmoking+nondrinking was used as the baseline (OR=1.0) , it was found that smoking+drinking was significantly associated with ESCC (OR:2.S,95%CI: 1.18-6.64).
5 The population attributable risk proportion (PARP) of smoking+drinking in ESCC, hyperplasia, and esophagitis groups was 36.8%, 11.5%, and 26.3% respectively.
6 Family history of ESCC was significantly associated with all the three kinds of esophageal lesions, with ORs of 2.0(95%CI: 1.09-3.60),1.8(95%CI: 1.27-2.45),1.8( 95%CI: 1.17-2.72) respectively. The OR for ESCC history of first-degree relatives was2.6(95%CI: 1.36-4.85) ,2. (95%CI: 1.43-2.99) and 1.8 (95%CI:1.13-3.03) in early ESCC, hyperplasia ,and esophagitis groups respectively.
7 To analyze the combined effect of ESCC family history with smoking, ESCC family history alone had no significant relation with ESCC, but the OR for ESCC family history+smoking was 3.3 (95%CI: 1.33-8.31)
8 To analyze the combined effect of ESCC family history with drinking, ESCC family history alone had no significant relation with ESCC, hyperplasia and esophagitis , but the ORs of family history+drinking were 5.8 ( 95%CI: 1.40-3.77) ,2.3 (95%CI: 2.21-15.04), 3.3 (95%CI: 1.73-6.33) for the three diseases respectively.
9 Meat increased the risk of ESCC, but soybean, fish, oil, celery, eggplant, kidney bean, green pepper, fat, crude fibre, ash and calcium decreased the risk; wheat, oil and heat were risk factors for esophageal hyperplasia, but leek had protective effect against it; oil and heat were risk factors for esophagitis.
10 If ALDH2 A/A genotype was used as the baseline (OR=1.0) , G/G genotype was significantly associated with atypical hyperplasia and basal cell hyperplasia, with OR the highest in basal cell hyperplasia group (6.6; 95%:CI: 2.19-20.07). To analyze the combined effect of genotype with drinking, nondrinking+A/A was used as the baseline (OR=1.0), drinking+G/G was significantly associated with atypical hyperplasia (OR=2.8; 95%:CI: 1.02-7.86) and basal cell hyperplasia (OR=16.1; 95%:CI: 2.01-129.39).
11 VDR genotype showed no significant relationship with all esophageal diseases, and no synthetic effect was found with smoking and drinking.4.12 The sAng-2 levels were 22.0±5.5, 21.3±3.2, 20.5±3.3, 24.0±5.0, and 29.8±5.0 U/ml in normal, esophagitis, hyperplasia, early ESCC, and advanced ESCC groups respectively. It was significantly higher in early ESCC than hyperplasia group (P=0.009).
12 The proportion of the level of sAng2 higher than normal was 7.7%, 6.8%, 2.4%, 23.1% and 78.6% respectively in esophagitis, hyperplasia, early carcinoma and advanced carcinoma groups. A positive correlation was found between serum Ang-2 level and ESCC process (r=0.206), suggesting that serum Ang-2 level increases with the development of esophageal disease.
Conclusions
1 Traditional epidemiology investigation found that risk factors for nonmalignant, precancerous and cancerous diseases were different. The results were: (1) ESCC: smoking, drinking and family history of ESCC; (2) hyperplasy: smoking and family history of ESCC; (3) esophagitis: drinking and family history of ESCC. Diet and nutritional ingredient had association with all esophageal diseases. There was interaction between drinking, smoking and family history at all stages of the disease.
2 The environment-gene analysis found that risk factors for nonmalignant, precancerous and cancerous diseases were different too. ALDH2 G/G had association with atypical hyperplasia and base cell hyperplasia, the combination of G genotype with smoking increases the risk of ESCC and atypical hyperplasia, and ALDH2 G/G interacted with drinking at all stages of esophageal diseases. VDR genetype had no association with esophageal diseases.
3 Traditional epidemiology investigation found that the ORs of various risk factors in ESCC group were higher than that in esophagitis and hyperplasy group. While the ALDH2-environment analysis found that the effect of risk factors was more evident in the hyperplasy group.
4 The level of the antibodies against sAng2 had some association with precarcinomaous lesion of esophageal epithelium mucosa and it may be useful to the long-term monitoring of high risk individuals.
Meaning and creativity
1 In this study, the controls and patients came from the same community of high incidence of ESCC, and they possessed similar environment and customs, so their data are comparable. All diseases are determined by endoscope and pathological examination, and the possibility of misclassification is small. All patients were newly found, so they provided information with little recall bias, and their lifestyle, such as smoking and drinking did not change because of the disease. In a word, the results of this study is dependable.
2 According to the development process of ESCC, we designed the multiple sequence case-control study. The influencing factors of each stage were analyzed by the combination of traditional and molecular epidemiology. The result will be helpful to learn the pathological process of ESCC and provide epidemiology method for ESCC prevention in high-incidence areas. Furthermore, no report was found about the systemic study on the factors of precancerous esophageal diseases in high-incidence aeras, so the result can provide scientific proofs to prevent precancerous diseases in these areas.
Shortcomings and suggestions
1 Shortcomings
1.1 When the influencing factors were combined to analyze, some layers had not enough samples to estimate their ORs, so the result in the present study should be validated in the further studies.
1.2 The samples for the two genes were not completely same and their synthetic effect was not analyzed.
2 Suggestions
In order to establish a dynamic monitoring system for high-risk individuals and find ideal indexes for early screening of ESCC, we suggest studying the development of nonmalignant esophageal diseases, make intervention in high-incidence areas and observe the change of some biological markers.
食管癌是世界上最常见的六大恶性肿瘤之一，我国每年约有25万新诊断的病例，占全世界病例数的一半。在河南、山西、河北三省交界的太行山南侧地区，其发病率高达100／10万以上。河南省林州市(原林县)和河北省磁县是我国、也是世界上食管癌发病率和死亡率最高的地区。此外，我国其他地区，如福建省安溪县、广东省南澳县、江苏省淮安市、四川省盐亭县、山东省肥城市等的食管癌发病率也较高。
食管上皮癌变是一个多阶段、进行性衍变的过程，正常食管上皮由于某种原因的刺激产生炎症，然后到炎性增生，再发展为不典型增生，进一步发展为癌。食管癌前病变突出的临床特征是其双向发展不稳定特性，即其可向癌的方向持续发展，也可以停留在某一阶段多年不变，甚至可以退回到正常状态。
从20世纪70年代以来，在食管癌高发区进行普查发现，其他食管疾病的患病率也非常高。如1983年在河南省林县由12649人参加的食管脱落细胞学拉网检查发现，基底细胞增生、轻度不典型增生、中度不典型增生、近癌及食管癌的检出率分别为38％、21％、6％、2％、2％。其他食管疾病与食管癌有相同的影响因素，如男性慢性食管炎的检出率高于女性，有食管癌家族史者慢性食管炎检出率明显高于无食管癌家族史者。另外，轻度增生、重度增生和食管癌的平均患病年龄依次增高，表明食管增生是食管癌的必经阶段。
对不同地区、不同时间进行的比较研究发现，食管癌及其衍变的各个阶段的检出率有一致的表现。食管癌高发区食管炎症、基底细胞增生及不典型增生的检出率高于低发区。1980年和2004年对河南省林州市同一地区居民进行的食管内镜与组织学检查发现，两次食管癌检出率无统计学差异，而非典型性增生表现出相同的结果，也未发现有统计学差异。
在高发区进行的前瞻性研究发现，食管炎症、增生与食管癌具有明显的联系。在河南省高发区进行的30—78个月随访研究发现，单纯炎症或增生患者的食管癌发病率为4.03％，而不典型增生患者的发病率高达33.87％。另一项15年的随访研究发现，正常食管黏膜、轻度不典型增生、中度不典型增生、重度不典型增生发展为食管癌的率依次增高，分别为2.4％、5.0％、8.3％、10.3％。
对食管癌手术标本的观察发现，从癌旁组织中可以看到，单纯性增生、不典型增生到原位癌的发展过程，而且癌旁组织的种类与食管癌的分化程度有关。对大白鼠、犬等实验动物给予致癌物质，也观察到了食管先后经过基底细胞增生、不典型增生，然后发展为癌的过程。在河南省林县进行的一项干预研究中，食管重度增生患者服用核黄素，取得了较好的远期效果，试验组的的癌变率低于对照组，差异有统计学意义，说明对食管不同衍变阶段的干预治疗，是预防食管癌发病的一条有效途径。总之，有明显的证据表明，食管癌的发展是一个多阶段的过程，研究其衍变的规律及各阶段的影响因素，对预防食管癌的发生具有重要的理论和实践意义。
传统流行病学对食管癌的流行病学特征及影响因素研究发现，食管癌的发病与性别、年龄有关，且存在明显的地理分布特点：农村高于城市、山区高于平原。其影响因素包括生活习惯(如吸烟、饮酒)、肿瘤家族史、饮食结构等。但传统流行病学难以对高危险性个体中仅仅很少的人会发病做出解释。随着基因学的发展，人们开始认识到这种现象可能与基因遗传易感性不同有关。从代谢酶基因、DNA修复基因、抑癌基因和癌基因突变研究与食管癌发生的关联，已成为分子流行病学研究重点之一。
促血管生成素2(angiopoietin 2，Ang2)是较受关注的广谱肿瘤标志物，对临床手术标本研究发现，Ang2在食管癌中的表达高于癌旁及周围对照组织，但未见随着食管癌前病变等级增加患者血清Ang2水平是否升高的报道。
目前已经报道的食管癌影响因素主要来自病例对照研究，病例为食管癌患者，对照多为一般人群或医院非癌患者，而选择的对照往往没有经过食管黏膜是否正常的检查，难免产生由对照选择引入的偏倚。对食管非恶性疾病及食管癌前病变的影响因素的研究鲜有报道，更没有见到在高发社区同时进行多阶段食管癌前疾病和食管癌的病例对照研究。因此，有必要对同一群体不同食管疾病的危险因素进行研究，为食管癌的一级预防和二级预防提供理论依据；同时也有利于发现与食管癌变阶段有关联的生物标志物，以便为危险个体的动态监测提供评价指标。
20世纪70年代到90年代，山东省进行过3次恶性肿瘤回顾调查，资料分析显示，食管癌的高发区局限在肥城市和宁阳县，其周围县市为偏高区。全省1990—1992年恶性肿瘤死因排序表明，食管癌死亡率为18.22／10万人口，居第4位，占所有恶性肿瘤死亡的15.44％。1970—1974、1985—1989、1990—1992、1997—1999年4个时期肥城市食管癌死亡率分别为63.19／10万(以下略去／10万)、71.68、66.87和82.33；标化死亡率(以1964年中国人口标化)分别为45.37、46.67、51.21、46.32，呈平稳状态。男女比例为2：1。2000—2004年死亡率为71.07，标化死亡率为34.64。从标化率的变化看，近年来有下降的趋向。
肥城市食管癌尚未进行病因干预，多年来仅进行了死亡监测和高低发区对比研究。1999年建立了肿瘤发病死亡登记报告制度；2003年被列为山东省可持续发展十大科技示范工程之一，在该地开展食管癌的早期筛查防治研究。
研究目的
首先采用传统流行病学和分子流行病学方法，分析食管癌前不同疾病阶段的影响因素；然后采用基因-环境设计，研究乙醛脱氢酶2(aldehyde dehydrogenase 2，ALDH2)基因、维生素D基因受体(vitamin D receptor，VDR)基因的多态性与食管癌前不同疾病的关联；并对可能与癌衍变阶段有关联的生物标志物sAng2的水平进行了检测；以便为预防食管疾病的发生，制订降低高危人群食管癌发病率的措施提供理论依据。
研究方法
1食管癌不同衍变阶段的定义本研究所指的食管癌均为食管鳞癌，将其不同衍变阶段定义为：食管黏膜上皮正常—食管炎—基底细胞增生—不典型增生(轻度、中度、重度)—早期癌(含原位癌)—晚期癌。
2食管癌不同衍变阶段的影响因素2004年10月—2005年10月，对肥城市—乡镇40—69岁人群作免费内镜普查。内容包括(1)问卷调查：包括性别、年龄、文化程度、婚姻状况、职业、家庭人年均收入等一般情况；肿瘤家族史(胃癌、食管癌、其他肿瘤)；行为习惯(吸烟、饮酒等)；饮食情况(主副食、蔬菜、水果)；(2)采集空腹外周血5ml，按RT-PCR方法要求分离和保存血清和血粒细胞；(3)消化内镜(电子内镜)检查，对未染色部分取活检组织作病理学检查，结果分为正常、炎症、基底细胞增生、轻度不典型增生、中度不典型增生、重度不典型增生、原位癌、早期癌。将早期癌、增生、炎症患者分别作为指示病例组，癌组由普查发现病例和住院病例两部分组成，内镜检查正常食管黏膜为指示对照组。描述各种食管疾病的流行病学特征，分析吸烟、饮酒、肿瘤家族史、饮食及其营养成分在不同食管病变的频数分布与作用。
3 ALDH2基因、VDR基因与食管癌不同衍变阶段易感性的关联从食管癌、不典型增生、基底细胞增生、炎症、正常者中抽取部分样本，提取DNA，检测与酒精代谢有关的ALDH2基因、与营养素代谢有关的VDR基因的多态性。另外，还分析了2种基因与吸烟、饮酒相结合对食管疾病的影响。
4 sAng2与食管癌衍变阶段的关联选取正常人、炎症、增生、早期食管鳞癌和晚期食管鳞癌患者血清共261份，进行Ang2测定，分析其与癌变各阶段的关联。
5统计学处理定性指标采用相对数比较，显著性检验用x~2检验。采用多项式Logistic回归分析危险因素，观察指标为比值比(OR)及其95％可信区间(95％CI)。以(?)±s表示sAng2水平，采用方差分析比较各组差别，采用等级相关分析其与癌变阶段的相关性。
数据录入及分析利用SPSS12.0软件完成。
主要研究结果
1共3253人参加内镜普查，其中5例资料不全未用于分析。从中发现食管早期癌20例、增生266例、炎症144例和食管黏膜正常2818例。鉴于早期癌病例较少，为了增加样本量，加入了在肥城市人民医院接受住院治疗的51例食管癌患者的资料，与普查得到的早期癌病例合为癌组分析。性别、年龄、文化水平、人年均收入在各组人群间存在统计学差异，婚姻状况、职业无统计学差异。
2吸烟与不吸烟比较，OR在食管癌组最高，但未达到显著性水平。按吸烟指数分析，吸烟指数＞500在食管癌组和增生组的OR分别为2.3(95％CI：1.10—4.86)和1.5(95％CI：1.01—2.18)，均达到显著性水平。
3饮酒与不饮酒比较，饮酒在食管癌、炎症组OR分别为2.8(95％CI：1.35—5.76)和1.8(95％CI：1.08—5.87)，达到显著性水平。按饮酒指数分析，在饮酒指数＞30和≤30两个水平上，均与食管癌组有关联，OR分别为3.1(95％CI：1.35—5.76)和2.5(95％CI：1.12—5.69)，并显示出“剂量-效应”趋向。饮酒指数≤30在炎症组OR也达到显著性水平。
4将吸烟和饮酒结合分析，以不吸烟+不饮酒为比较的基线水平(OR=1.0)，吸烟+饮酒与食管癌有显著性关联，OR为2.8(95％CI：1.18—6.64)。
5将对照组吸烟和饮酒暴露率作为人群中暴露的参数，吸烟+饮酒在食管癌、增生、炎症的人群归因危险百分比(PARP)分别为36.8％、11.5％、26.3％。
6有食管癌家族史在食管癌、增生、炎症组的OR分别为2.0(95％CI：1.09—3.60)、1.8(95％CI：1.27—2.45)、1.8(95％CI：1.17—2.72)；按亲缘系数分析，一级血亲患食管癌在3组的OR分别为2.6(95％CI：1.36—4.85)、2.1(95％CI：1.43—2.99)、1.8(95％CI：1.13—3.03)。
7将食管癌家族史与吸烟结合分析，单独有食管癌家族史与食管癌无显著性关联，而有食管癌家族史+吸烟的OR为3.3(95％CI：1.33—8.31)。
8将食管癌家族史及饮酒结合分析，仅有食管癌家族史在食管癌、增生、炎症组的OR均未达到显著性水平，但合并饮酒后均达到显著性水平，且明显升高，OR分别为5.8(95％CI：1.40—3.77)、2.3(95％CI：2.21—15.04)、3.3(95％CI：1.73—6.33)。
9肉类是食管癌的危险因素，大豆、鱼类、油类、芹菜、茄子、芸豆、青椒、脂肪、粗纤维素、灰分、钙能降低其危险性；小麦、油类、热量是食管增生的危险因素，韭菜具有预防作用；油类、热量是食管炎症的危险因素。
10分析ALDH2与不同食管疾病的关联，以A／A型基因作为比较的基线，G／G型OR在不典型增生、基底细胞增生组达到显著性水平，其中在基底细胞增生组最高，为6.6(95％CI：2.19—20.07)。以不吸烟+A／A作为比较的基线(OR=1.0)，发现G基因型与吸烟结合增加癌和不典型增生组的危险性，其中癌组ALDH2 G／A型OR为12.7(95％CI：1.62-100.70)，有发现G基因型与吸烟结合增加食管炎症或基底细胞增生的危险性。将基因型与饮酒结合分析，以不饮酒+A／A作为比较的基线(OR=1.0)，饮酒+G／G在不典型增生组和基底细胞增生组达到显著性水平，OR分别为2.8(95％CI：1.02—7.86)和16.1(95％CI：2.01—129.39)。
11分析VDR基因型与食管疾病的关系，与T／t比较，T／T的OR在食管癌、不典型增生、基底细胞增生和炎症组均未达到显著性水平，也未发现VDR基因型与吸烟、饮酒的交互作用。
12按sAng2试剂盒说明书规定，正常、炎症、增生、早期癌、中晚期癌高出正常值的比例分别为7.7％、6.8％、2.4％、23.1％、78.6％。相关分析显示，sAng2与癌变过程指示变量的等级相关系数为0.206，P＜0.01(双尾)，二者存在正相关，有统计学意义；但属于低度相关，表明sAng2随着疾病向癌变等级增加血清中的表达水平增高。
结论
1传统流行病学分析发现食管非恶性疾病、癌前病变和癌的危险因素有差异，分别是：(1)癌：吸烟、饮酒、食管癌家族史；(2)增生：吸烟、食管癌家族史；(3)炎症：饮酒、食管癌家族史。饮食及其营养成分与各种食管疾病均有关联。在各不同疾病阶段都存在吸烟、饮酒及食管癌家族史三者之间的交互作用。
2基因-环境分析发现食管非恶性疾病、癌前病变和癌的危险因素也有差异。ALDH2 G／G型与癌前不典型增生、基底细胞增生有关联，G基因型与吸烟结合增加癌和不典型增生组的危险性。ALDH2 G／G型及饮酒在食管各不同疾病阶段中都有交互作用。没有发现VDR基因与食管各阶段疾病有关联。
3传统流行病学分析表明，各种危险因素在癌组的OR大于炎症组及增生组；而ALDH2基因与环境因素的研究表明，各种危险因素对食管增生的影响较为明显。
4 sAng2水平与食管黏膜上皮癌前病变程度有一定关联，可能对高危险个体长期监测有一定意义。
意义与创新
1本研究选取一食管癌高发乡镇进行碘染色内镜检查，对照组与病例组来自同一人群，他们拥有相同或相似的生活环境、风俗习惯，具有较好的可比性。病例及对照均经染色内镜或／和组织病理学确诊，误分类的可能性极小，且为新发病例，提供的信息一般不存在回忆偏倚，生活尚未因发病而改变。因此，本研究结果可靠。
2按照食管鳞癌衍变的不同阶段疾病，采用多序列病例-对照研究分析和分子流行病学基因遗传多态性与环境因素分析各个阶段发生的危险因素，将传统流行病学与分子流行病学结合起来观察食管癌不同衍变阶段的影响因素，不仅对理解食管癌发生过程有病理生理性学术意义，可为高发区疾病预防提供新的流行病学研究途径，更重要的是可以为癌前疾病阶段开展防治提供科学依据。
国内外目前尚未见在高发区同时对食管癌衍变不同阶段危险因素进行研究的报道。
不足与建议
不足：
1检出的食管癌不同衍变阶段疾病的样本数尚不足够大，本研究的发现有待进一步增大样本量进行考察。
2检测2种基因型时，测定的样本例数不完全一致，没有进行2种基因的交互作用分析。
建议：
对检出的各个阶段非恶性疾病进行动态监测，观察食管癌不同衍变阶段的发展变化，并能进行干预性研究以及观测某些生物标志物的变化，为建立高危险人群动态监测及癌的早期筛查指标提供契机。
Esophageal squamous cell carcinoma (ESCC) is one of the most common carcinomas in the world. There are about 250 000 newly diagnosed patients with ESCC every year, ranking the 4th in carcinomas in China. Most areas have a low prevalence in China, but the south area of the Taihang Mountain, which is the boundary of He'nan, Shanxi, and Hebei has a high prevalence of 100/100 000. Linzhou City (originally named as Lin County) and Ci County have the highest prevalence and mortality of ESCC in China, as well as in the world. Furthermore, several other areas in China, such as Anxi County in Fujian Province, Nan'ao County in Guangdong Povince, Huai'an City in Jiangsu Province, Yanting County in Sichuan Province and Feicheng City in Shandong Province have high prevalence of ESCC too.
The clinical characteristics of precancerous esophageal leasions are bidirectional and inconstant. In other words, the lesions may either develop into a carcinoma or stay in a certain stage for quite many years, even turn to normal status.
Some investigations ever since 1970s have revealed the fact that the prevalence of other esophageal diseases is also higher in areas with high prevalence of ESCC than in other areas.
An esophageal balloon-cytology screening was carried out in Lin County. Among the 12649 participants 38% showed hyperplasia, 21% showed atypical hyperplasia 1, 6% showed atypical hyperplasia 2, 2% showed near-carcinoma and 2% showed carcinoma. ESCC and other esophageal diseases have common risk factors. For instance, the prevalence rate of ESCC is higher in males than in females, and the prevalence rate of chronic esophageal inflammation is higher in males too; the prevalence rate is high in those who have an ESCC family history. The age of patients with gentle atypical hyperplasia, severe atypical hyperplasia and carcinoma gradually increased, indicating esophageal atypical hyperplasia is a transitional stage of ESCC.
Many comparative studies between different areas or periods showed that the prevalence of ESCC is accordant with the prevalence of non-malignant esophageal diseases. The prevalence of esophageal inflammation, base cell hyperplasia and atypical hyperplasia is higher in areas with a high carcinoma rate than in areas with a low carcinoma rate. Two studies carried out in Linzhou City in 1980 and 2004 respectively found that there was no significant difference in ESCC prevalence, and that there was no significant difference in atypical hyperplasia prevalence too.
Prospective studies in areas with high ESCC rate demonstrated the significant correlation between esophagitis, base hyperplasia and ESCC. A follow-up study of 30-78 months in the high incidence area of He'nan Province showed that 4.03% of the patients with esophagitis or simple hyperplasia and 33.87% of the patients with atypical hyperplasia developed ESCC. Another 15-year-follow- up revealed that the incidence rate of normal esophageal mucosa, gentle atypical hyperplasia, moderate atypical hyperplasia and severe atypical hyperplasia to ESCC are as follows, 2.4%, 5.0%, 8.3% and 10.3%, respectively.
Through the observation on surgery specimens the developing process of ESCC can be found from simple hyperplasia to atypical hyperplasia and carcinoma in situ, and the features of surrounding tissues are related to the differentiation of ESCC. Many experimental studies on animals such as rats or dogs also demonstrated this process. One intervention study in Lin County showed that patients with severe hyperplasia subjected to drug interruption had a lower prevalence of ESCC than the control group, suggesting that intervention therapy on non-malignant esophageal lesions is effective to prevent ESCC. Obviously, it is important to study the development and risk factors of non-malignant lesions to decrease the prevalence and mortality of ESCC.
ESCC is related with age and sex and geographical environment, with a higher incidence in countryside than cities and a higher incidence in mountain area than in champaign. Its influencing factors include life habits (such as smoking and drinking), carcinoma family history, and diet etc. It is difficult to calculate the disease probability to an individual only using traditional epidemiology. For example, among the people who smoke, drink and have a family history of ESCC, only a few develop ESCC. This phenomenon is caused by different hereditary susceptibilities, so it is necessary to study the influencing factors on the level of molecular biology.
Studies on surgery specimens showed that angiopoietin-2 (Ang2) is highly expressed in many carcinoma tissues. It has been reported that Ang2 is higher in ESCC tissues than in surrounding and normal tissues, but no information about the Ang2 level is reported in the serum of different esophagus diseases.
Studies on influencing factors of ESCC mostly adopt case-control designs, in which the experiment group consisted of pathologically diagnosed patients and the control group consisted of healthy people or non-carcinoma inpatients. Selection bias was inevitable in these studies because the esophagus mucosa of the controls were not examined. The influencing factors of non-malignant esophageal lesions were seldom studied, and no multi-stage case-control study in a high incidence community was reported on precarcinomaous diseases and ESCC.
From 1970s to 1990s, malignant neoplasms investigations in Shandong Province were carried out for three times. The results showed that the prevalence rate of ESCC was high in Feicheng City and Ningyang County, relatively high in their surrounding areas and low in the east. A study in 1990-1992 showed that ESCC in Shandong Province accounted for 15.44% and ranked the 4~(th) in all carcinomas, with a mortality of 18.22/100000. The retrospective analysis showed that the mortality of ESCC in Feicheng City in 1970-1974, 1985-1989, 1990-1992, and 1997-1999 was 63.19, 71.68, 66.87 and 82.33/100,000 respectively, and the standard mortality (standardized by the population data of 1964 in China) was 45.37, 46.67, 51.21, 46.32/100000 respectively. The ratio of male to female was 2: 1. The mortality of ESCC was 71.07/100000 and the standard mortality was 34.64/100,000 in the period of 2000-2004, showing a declining incidence in recent years.
The death surveillance and comparative study with low prevalence areas have been carried out but no intervention has been given in Feicheng City. In 1999 the report system on carcinoma occurrences and deaths was established, and in 2003 it was authorized as one of the ten sustainable development model areas for the early screening and prevention of ESCC.
Objective
The purpose of the present study was to provide theoretical bases and suggestions to decline the ESCC incidence in people with high risk. The epidemiological characteristics and influencing factors of ESCC and other esophageal lesions were analyzed; the associations of aldehyde dehydrogenase-2 (ALDH2) and vitamin D receptor (VDR) genes with ESCC and other esophageal diseases were studied by a gene-environment design; and the level of angiopoietin-2 were detected in normal controls and patients with different esophageal lesions to calculate its possibility as a biomolecular marker.
Methods
1 Definition of different stages of ESCC
In the present study the esophageal carcinoma was referred as ESCC and its development process were divide into the following stages: normal mucosa, esophagitis, basal cell hyperplasia, displasia (mild, moderate, and severe), early carcinoma (including carcinoma in situ), and advanced carcinoma.
2 Risk factors for different stages of ESCC
From Oct. 2004 to Oct. 2005, the residents of 40-69 years old in a town of Feicheng City participated in a free screening program. Investigation contents were as follows: (1) Questionnaire investigation included general information, such as sex, age, .culture, marriage condition, profession, family average income; family history of gastric, esophageal and other carcinomas; life habits, such as smoking and drinking habits; and diet, such as staple food, non-staple food, vegetables, fruit and their nutrient elements. (2) 5 ml venous blood was collected at 9-10 am after a 12-h fast from each participant. The sample was centrifuged for 10 min at 3000 r/min to separate plasma and obtain blood cells. (3) I-staining esophageal endoscope examination was made by seasoned endoscope doctors. Subjects with normal esophageal mucosa consisted of control group and those whose esophageal tract was not I-stained were pathologically examined. The pathological results were classified into seven categories: esophagitis, basal cell hyperplasia, mild atypical hyperplasia, moderate atypical hyperplasia, severe atypical hyperplasia, carcinoma in situ, and early carcinoma. Cases of carcinoma (including some ESCC patients accepting surgery in Peoples' Hospital of Feicheng City), hyperplasia and esophagitis were selected as index groups respectively, and subjects with normal esophageal mucosa were selected as control group. The epidemiological features of esophageal diseases and the frequency distribution of possible influencing factors were analyzed and described.
3 Effect of ALDH2 and VDR genes on different stages of ESCC
Based on the results of esophageal endoscope and pathological examination, subjects were classified into 5 groups: ESCC, atypical hyperplasia, basal cell hyperplasia, esophagitis and normal. DNA of some samples was genotyped for ALDH2 and VDR polymorphisms. Reasons for choosing these two genes were that they are respectively associated with the alcohol metabolism and nutrition deficiency, which were found as two possible risk factors of ESCC in our former studies. In addition, given that smoking and drinking may be associated with esophageal diseases, the effect of the two genes combined with smoking and drinking was also analyzed.
4 Association of serum Ang-2 level with the process of ESCC
Serum Ang-2 of 261 normal subjects, patients with esophagitis, hyperplasia, early carcinoma and advanced carcinoma was tested to analyzed.
5 Statistical analysis
Qualitative data were compared by relative ratio and chi-square test was used to evaluate differences in the frequency distributions of various potential risk factors among different stages of ESCC. Polynomial Logistic regression was used to analyze risk factors. The observation indexes were odds ratios (ORs) and 95% confidence intervals (95%C/s). The serum angiopoietin-2 level was described as (x|-)±s. ANOVA was used to compare the differences among different groups. The association of serum Ang-2 with the process of ESCC were calculated with rank correlation .
All data were input and analyzed by SPSS 12.0.
Results
1 A total of 3253 subjects participated in the enscope screening. Data from 5 cases were incomplete and were excluded. The examination result was as follows: early carcinoma, 20; hyperplasia, 266; esophagitis, 144; and normal mucosa, 2818. In addition, we selected 51 inpatients with ESCC, so the carcinoma group included 71 patients. There were significant differences among different groups in terms of sex, age, culture and family average income. However, there were no differences in terms of marriage or occupation.
2 After adjustment of sex, age, culture, and family average income, the OR ofsmoking to nonsmoking was the highest in ESCC group but had no statisticalsignificance. The OR of smoking index >500 was 2.3 (95%CI: 1.10-4.86) and 1.5(95%CI: 1.01-2.18) in ESCC group and hyperplasia group respectively, which reached the significant level.
3 The OR of drinking to nondrinking in ESCC group and hyperplasia group was 2.8 (95%CI: 1.35-5.76) and 1.8 (95%CI: 1.08-5.87) respectively, which reached the significant level. According to drinking index, drinking was associated with ESCC in >30 and <30 levels, with ORs of 3.1 (95%CI: 1.35-5.76) and 2.5(95%CI: 1.12-5.69) respectively. In addition, OR of drinking index <30 reached significant level in esophagitis group.
4 If nonsmoking+nondrinking was used as the baseline (OR=1.0) , it was found that smoking+drinking was significantly associated with ESCC (OR:2.S,95%CI: 1.18-6.64).
5 The population attributable risk proportion (PARP) of smoking+drinking in ESCC, hyperplasia, and esophagitis groups was 36.8%, 11.5%, and 26.3% respectively.
6 Family history of ESCC was significantly associated with all the three kinds of esophageal lesions, with ORs of 2.0(95%CI: 1.09-3.60),1.8(95%CI: 1.27-2.45),1.8( 95%CI: 1.17-2.72) respectively. The OR for ESCC history of first-degree relatives was2.6(95%CI: 1.36-4.85) ,2. (95%CI: 1.43-2.99) and 1.8 (95%CI:1.13-3.03) in early ESCC, hyperplasia ,and esophagitis groups respectively.
7 To analyze the combined effect of ESCC family history with smoking, ESCC family history alone had no significant relation with ESCC, but the OR for ESCC family history+smoking was 3.3 (95%CI: 1.33-8.31)
8 To analyze the combined effect of ESCC family history with drinking, ESCC family history alone had no significant relation with ESCC, hyperplasia and esophagitis , but the ORs of family history+drinking were 5.8 ( 95%CI: 1.40-3.77) ,2.3 (95%CI: 2.21-15.04), 3.3 (95%CI: 1.73-6.33) for the three diseases respectively.
9 Meat increased the risk of ESCC, but soybean, fish, oil, celery, eggplant, kidney bean, green pepper, fat, crude fibre, ash and calcium decreased the risk; wheat, oil and heat were risk factors for esophageal hyperplasia, but leek had protective effect against it; oil and heat were risk factors for esophagitis.
10 If ALDH2 A/A genotype was used as the baseline (OR=1.0) , G/G genotype was significantly associated with atypical hyperplasia and basal cell hyperplasia, with OR the highest in basal cell hyperplasia group (6.6; 95%:CI: 2.19-20.07). To analyze the combined effect of genotype with drinking, nondrinking+A/A was used as the baseline (OR=1.0), drinking+G/G was significantly associated with atypical hyperplasia (OR=2.8; 95%:CI: 1.02-7.86) and basal cell hyperplasia (OR=16.1; 95%:CI: 2.01-129.39).
11 VDR genotype showed no significant relationship with all esophageal diseases, and no synthetic effect was found with smoking and drinking.4.12 The sAng-2 levels were 22.0±5.5, 21.3±3.2, 20.5±3.3, 24.0±5.0, and 29.8±5.0 U/ml in normal, esophagitis, hyperplasia, early ESCC, and advanced ESCC groups respectively. It was significantly higher in early ESCC than hyperplasia group (P=0.009).
12 The proportion of the level of sAng2 higher than normal was 7.7%, 6.8%, 2.4%, 23.1% and 78.6% respectively in esophagitis, hyperplasia, early carcinoma and advanced carcinoma groups. A positive correlation was found between serum Ang-2 level and ESCC process (r=0.206), suggesting that serum Ang-2 level increases with the development of esophageal disease.
Conclusions
1 Traditional epidemiology investigation found that risk factors for nonmalignant, precancerous and cancerous diseases were different. The results were: (1) ESCC: smoking, drinking and family history of ESCC; (2) hyperplasy: smoking and family history of ESCC; (3) esophagitis: drinking and family history of ESCC. Diet and nutritional ingredient had association with all esophageal diseases. There was interaction between drinking, smoking and family history at all stages of the disease.
2 The environment-gene analysis found that risk factors for nonmalignant, precancerous and cancerous diseases were different too. ALDH2 G/G had association with atypical hyperplasia and base cell hyperplasia, the combination of G genotype with smoking increases the risk of ESCC and atypical hyperplasia, and ALDH2 G/G interacted with drinking at all stages of esophageal diseases. VDR genetype had no association with esophageal diseases.
3 Traditional epidemiology investigation found that the ORs of various risk factors in ESCC group were higher than that in esophagitis and hyperplasy group. While the ALDH2-environment analysis found that the effect of risk factors was more evident in the hyperplasy group.
4 The level of the antibodies against sAng2 had some association with precarcinomaous lesion of esophageal epithelium mucosa and it may be useful to the long-term monitoring of high risk individuals.
Meaning and creativity
1 In this study, the controls and patients came from the same community of high incidence of ESCC, and they possessed similar environment and customs, so their data are comparable. All diseases are determined by endoscope and pathological examination, and the possibility of misclassification is small. All patients were newly found, so they provided information with little recall bias, and their lifestyle, such as smoking and drinking did not change because of the disease. In a word, the results of this study is dependable.
2 According to the development process of ESCC, we designed the multiple sequence case-control study. The influencing factors of each stage were analyzed by the combination of traditional and molecular epidemiology. The result will be helpful to learn the pathological process of ESCC and provide epidemiology method for ESCC prevention in high-incidence areas. Furthermore, no report was found about the systemic study on the factors of precancerous esophageal diseases in high-incidence aeras, so the result can provide scientific proofs to prevent precancerous diseases in these areas.
Shortcomings and suggestions
1 Shortcomings
1.1 When the influencing factors were combined to analyze, some layers had not enough samples to estimate their ORs, so the result in the present study should be validated in the further studies.
1.2 The samples for the two genes were not completely same and their synthetic effect was not analyzed.
2 Suggestions
In order to establish a dynamic monitoring system for high-risk individuals and find ideal indexes for early screening of ESCC, we suggest studying the development of nonmalignant esophageal diseases, make intervention in high-incidence areas and observe the change of some biological markers.
引文
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