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.
引文
1 林东昕,谭文,陆士新,邢德印.中国食管癌分子流行病学研究.中华流行病学杂志,2003,24(10):939-943.
2 Yang L, Parkin DM, Li L, Chen Y. Time trends in cancer mortality in China: 1987-1999. Int J Cancer, 2003, 106: 771-783.
3 贺宇彤,侯浚,陈志峰,张国生.河北磁县食管癌早诊早治效果预测.中国慢性病预防与控制,2003,11(2):54-55.
4 黄丽芳,史习舜,田俊,周艳丽,周紫荆,李国梁.福建省安溪县食管癌的遗传流行病学研究.中国肿瘤,2006,15(1):7-9.
5 林昆,张国恺,朱碧柳,戴杰民.广东食管癌高低发区烟酒消费与食管癌的关系,疾病控制杂志,2006,10(1):5-7.
6 潘恩春,杨文洲,胡旭,开海涛,王仪.江苏省淮安市楚州区食管癌危险因素病例对照研究,疾病控制杂志,2006,10(2):114-116.
7 陶德明,胥永忠,王旭华,顾元凯,王德易,王天秀.417例食管上皮细胞重度增生随访性研究.河南肿瘤学杂志,1997,10(1):38-39.
8 赵德利,杨友德,陈明会,胡茂新,张泉河,郭晓路,李会庆,金世宽.肥城市食管癌的危险因素研究.肿瘤防治杂志,2003,10(1):27-30.
9 Voutilainen ME, Juhola MT. The changing epidemiology of esophageal cancer in Finland and the impact of the surveillance of Barrett's esophagus in detecting esophageal adenocarcinoma. Dis Esophagus, 2005, 18(4):221-5.
10 王福生,单际平,蒋丹斌,朱建清,张汉仁.食管癌发病特点的变化.胃肠病学和肝病学杂志,2002,11(3):256-257.
11 韦开珍.普陀区1994-2003年食管癌发病率分析.中华临床医学卫生杂志,2006,4(8):21-23.
12 Marmo R, Rotondano G, Piscopo R, Bianco MA, Russo P, Capobianco P, Cipolletta L. Combination of age and sex improves the ability to predict upper gastrointestinal malignancy in patients with uncomplicated dyspepsia: a prospective multicentre database study. Am J Gastroenterol, 2005, 100(4):784-91.
13 全培良,刘曙正,戴涤新,孙喜斌,陆建邦.河南省1984-2002年食管癌死亡率分析.中国肿瘤,2004,13(5):290-291.
14 张兆祥.吸烟饮食与食管癌的研究进展.中国公共卫生,2003,19(3):359-361.
15 Shen O, Liu SF, Dawsey SM, Cao J, Zhou B, Wang DY, Cao SG, Zhao HZ, Li GY, Taylor PR. Cytologic screening for esophageal cancer: results from 12,877 subjects from a high-risk population in China. Int J Cancer 1993;54:185-8.
16 侯浚;林培中;陈志峰;王国清;刘恬格;李绍森;孟凡书;杜成林.磁县食管癌普查研究,肿瘤防治研究,1998,25(1):73-75.
17 陶德明.四川盐亭县15万人群食管癌普查食管上皮增生与癌的患病年龄分析.肿瘤防治,1991,1:23-24.
18 杨观瑞,赵立群.中国食管癌高发区人群的内镜普查—食管癌的早期诊断自然史和发症学研究.内镜,1991,8(1):2-4.
19 付华民,任金萍.食管癌高低发区人群食管粘膜组织病理学研究.新乡医学院学报,1998,15(3):204-206.
20 张亚冰,赵立群,裘宋良,张聚真,裘一兵,杨静,杨观瑞,薛乐勋.河南省林州市2004与1980年食管癌前病变和食管癌患病率的比较研究.中华肿瘤防治杂志,2006,13(5):328-330.
21 Guanrei Y, Songliang Q. Endoscopic surveys in high-risk and low-risk populations for esophageal cancer in China with special reference to precursors of esophageal cancer. Endoscopy, 1987, 19: 91-5.
22 Wang LD, Yang HH, Fan ZM, Lu XD, Wang JK, Liu XE, Sun Z, Jiang YN, He X, Zhou Q. Cytological screening and 15 years' follow-up (1986-2001) for early esophageal squamous cell carcinoma and precancerous lesions in a high-risk population in Anyang County, Henan Province, Northern China. Cancer Detect Prev, 2005, 29:317-22.
23 Lu JB, Yang WX, Dong WZ, Sang JY. A prospective study of esophageal cytological atypia in Linxian county. Int J Cancer, 1988, 41:805-8.
24 陈志峰,俟浚,张建慧,贺宇彤.食管鳞状上皮细胞重度不典型增生研究进展.河南肿瘤学杂志,2004,17(1):72-73.
25 Takeshita K, Sunagawa M, Nakajima A, Ochi K, Habu H, Hoshi K. Endoscopic and histopathological studies of experimental esophageal cancer in beagles. Nippon Geka Gakkai Zasshi, 1985, 86:139-47.
26 Sasajima K, Taniguchi Y, Okazaki S, Morino K, Takubo K, Yamashita K, Shirota A.. Sequential morphological studies of the esophageal carcinoma of rats induced by N-methyl-N-amylnitrosamine. Eur J Cancer Clin Oncol, 1982, 18:559-64. ()
27 于红玉,宋中朝.846例食管上皮重增的治疗分析.实用肿瘤学杂志,1990,4(3):23-26.
28 范金虎,孙秀娣,张亚黎,乔友林.吸烟与食管癌发病关系的前瞻性研究.肿瘤研究与临床,2004,16(4):286-288.
29 么鸿雁,陈辉,吕美霞,余红平,杨念念,方亚,段纪俊,施侣元.行为生活方式对恶性肿瘤发病影响的综合分析.中国公共卫生,2003,19(4):407-408.
30 刘伯齐,姜晶梅,陈铮鸣,陈君石,张孔来,曾宪嘉,赵平.中国103个地区吸烟与食管癌风险研究:死因调查中的病例对照方法学研究.中华医学杂志,2006.86(6):380-385.
31 Tran GD, Sun XD, Abnet CC, Fan JH, Dawsey SM, Dong ZW, Mark SD, Qiao YL, Taylor PR. Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int J Cancer, 2005, 113(3):456-63.
32 Zambon P, Talamini R, La Vecchia C, Dal Maso L, Negri E, Tognazzo S, Simonato L, Franceschi S. Smoking, type of alcoholic beverage and squamous cell oesophageal cancer in northern Italy. Int J Cancer, 2000, 86(1): 144-149.
33 Saeki H, Ohno S, Araki K, Egashira A, Kawaguchi H, Ikeda Y, Morita M, Kitamura K, Sugimachi K. Alcohol consumption and cigarette smoking in relation to high frequency of p53 protein accumulation in oesophageal squamous cell carcinoma in the Japanese. Br J Cancer, 2000, 82(11): 1892-1894.
34 Gallus S, Bosetti C, Franceschi S, Levi F, Simonato L, Negri E, La Vecchia C. Esophageal cancer in women: tobacco, alcohol, nutritional and hormonal factors. Br J Cancer, 2001, 85(3):341-345.
35 Sakata K, Hoshiyama Y, Morioka S, Hashimoto T, Takeshita T, Tamakoshi A, JACC Study Group. Smoking, alcohol drinking and esophageal cancer: findings from the JACC Study. J Epidemiol, 2005, 15(Suppl 2):S212-9.
36 Bosetti C, Franceschi S, Levi F, Negri E, Talamini R, La Vecchia C. Smoking and drinking cessation and the risk of oesophageal cancer. Br J Cancer, 2000, 83(5): 689-691.
37 Leanderson P, Tagesson C. Cigarette smoke-induced DNA damage in cultured human lung cells: role of hydroxyl radicals and endonuclease activation. Chem Biol Interact, 1992, 81(1-2):197-208.
38 Boffetta P, Ye W, Adami HO, Mucci LA, Nyren O. Risk of cancers of the lung, head and neck in patients hospitalized for alcoholism in Sweden. Br J Cancer, 2001, 85(5): 678-682.
39 王立东;刘宾;冯常炜;张延瑞;张彦霞;李苹娟;常扶保;李吉林;高福生;冯笑山;高珊珊;何欣;范宗民;狄霞;吴会芳;焦新英;常志伟;王俊宽;刘小莉;邵珊;吕晓东;王苒;孙哲;周建伟;江亚南;杜芳;郭涛;李琮宇;刘卫娜;秦豫培;王能超;李韶华;周丽;温巍;张广平;郐大余;樊宇靖;杜娴娟.山西长治林州移民与河南林州居民食管、贲门和胃窦内镜病理结果比较.郑州大学学报:医学版,2006,41(1):5-9.
40 Chak A, Ochs-Balcom H, Falk G, Grady WM, Kinnard M, Willis JE, Elston R, Eng C. Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev, 2006, 15(9):1668-73.
41 Chak A, Lee T, Kinnard MF, Brock W, Faulx A, Willis J, Cooper GS, Sivak MV Jr, Goddard KA. Familial aggregation of Barrett's oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut, 2002, 51(3):323-8.
42 李琮宇;李节娟;吴会芳;郭涛;张彦霞;邵珊;王苒;常志伟;王智卿;杜芳;余炜伟;范宗民;王立东.河南食管癌高发区食管癌高癌家族调查.郑州大学学报(医学版),2006,41(1):32-34
43 Hemminki K, Rawal R, Chen B, Bermejo JL. Genetic epidemiology of cancer: from families to heritable genes. Int J Cancer, 2004, 111: 944-950.
44 王建明,徐飚,王理伟,华召来,周琴,李茂生.食管癌Y型核心家系宏观遗传流行病学研究.中国初级卫生保健,2003,17(10):60-61.
45 Bahmanyar S, Ye W. Dietary patterns and risk of squamous-cell carcinoma and adenocarcinoma of the esophagus and adenocarcinoma of the gastric cardia: a population-based case-control study in Sweden. Nutr Cancer, 2006, 54(2): 171-8.
46 Maley CC, Rustgi AK. Barrett's esophagus and its progression to adenocarcinoma. J Natl Compr Canc Netw, 2006, 4(4): 367-74.
47 Sammon AM, Iputo JE. Maize meal predisposes to endemic squamous cancer of the oesophagus in Africa: breakdown of esterified linoleic acid to the free form in stored meal leads to increased intragastric PGE2 production and a low-acid reflux. Med Hypotheses, 2006, 67(6): 1431-6.
48 Nakada, Y., Fattal E., Foulquier M, Couvreur P. Parmacokunetics and biodistribution of oligonucleotide absorbed onto poly isobutyl 1 cyanoarylate nanoparticle after intravenous administration in mice. Pharm Res, 1996, 13(1): 38-43.
49 戚光跃;苏士诚;尤春发;陈士伟;宋亚.食管癌发病影响因素病例对照研究.中国慢性病预防与控制,200l,9(1):15-16.
50 Han J. Highlights of the cancer chemoprevention studies in China. Prev Med, 1993, 22(5): 712-22.
51 陆云霞;施侣元;余红平;周素华.武汉市居民饮食模式与食管癌发病关系的条件logistic回归分析.中国卫生统计,2005,22(3):146-148.
52 李苏平;丁建华;高长明;周建农;吴建中;苏平;臧宇;刘燕婷;周学富;丁保国;王如鸿.上消化道肿瘤高发区胃癌、食管癌病例对照研究.肿瘤,2001,21(4):277-280.
53 王国清,郝长青,赖少清,王贵齐,吕宁,林冬梅,杨玲,谢永强.碘染色在食管癌高发区直接内镜普查中的应用和效果.中华消化内镜杂志,2003,20(6):377-379.
54 徐维衡.医学遗传学基础[M].北京:北京医科大学出版社.2003.141-142.
55 Badar F, Anwar N, Mahmood S. Geographical variation in the epidemiology of esophageal cancer in Pakistan. Asian Pac J Cancer Prev, 2005, 6(2): 139-42.
56 纪鹏,赵德利,尹承勇,雷复华,刁玉涛,陈丽,李会庆.1991-2004年肥城市食管癌病理组织学分型的变化趋势.中国肿瘤,2006,15(11):758-760.
57 de Jonge PJ, Steyerberg EW, Kuipers EJ, Honkoop P, Wolters LM, Kerkhof M, van Dekken H, Siersema PD. Risk factors for the development of esophageal adenocarcinoma in Barrett's esophagus. Am J Gastroenterol, 2006, 101(7):1421-9.
58 Wakhisi J, Patel K, Buziba N, Rotich J. Esophageal cancer in north rift valley of Western Kenya. Afr Health Sci, 2005, 5(2): 157-63.
59 Casson AG, Williams L, Guernsey DL. Epidemiology and molecular biology of Barrett esophagus. Semin Thorac Cardiovasc Surg, 2005, 17(4):284-91.
60 Jeon J, Luebeck EG, Moolgavkar SH. Age effects and temporal trends in adenocarcinoma of the esophagus and gastric cardia (United States). Cancer Causes Control. 2006 Sep; 17(7): 971-81.
61 Xibib S, Meilan H, Moiler H, Evans HS, Dixin D, Wenjie D, Jianbang L. Risk factors for oesophageal cancer in Linzhou, China: a case-control study. Asian Pac J Cancer Prev, 2003, 4(2): 119-24.
62 Jansson C, Johansson AL, Nyren O, Lagergren J. Socioeconomic factors and risk of esophageal adenocarcinoma: a nationwide Swedish case-control study. Cancer Epidemiol Biomarkers Prev, 2005, 14(7): 1754-61.
63 van Vliet EP, Eijkemans MJ, Steyerberg EW, Kuipers EJ, Tilanus HW, van der Gaast A, Siersema PD. The role of socio-economic status in the decision making on diagnosis and treatment of oesophageal cancer in The Netherlands. Br J Cancer, 2006, 95(9): 1180-5.
64 Wu IC, Lu CY, Kuo FC, Tsai SM, Lee KW, Kuo WR, Cheng YJ, Kao EL, Yang MS, Ko YC. Interaction between cigarette,, alcohol, and betel nut use on esophageal cancer risk in Taiwan. Eur J Clin Invest, 2006, 36(4):236-41.
65 Gao YT, McLaughlin JK, Blot WJ, Ji BT, Benichou J, Dai Q, Fraumeni JF Jr. Risk factors for esophageal cancer in Shanghai, China. I. Role of cigarette smoking and alcohol drinking. Int J Cancer, 1994, 58(2): 192-6.
66 Pera M, Manterola C, Vidal O, Grande L. Epidemiology of esophageal adenocarcinoma. J Surg Oncol, 2005, 92(3): 151-9.
67 闫增荣,罗荣,王秀琴,李兆志.张掖地区食管癌危险因素分析.兰州医学院学报,2001,27(3):33-37.
68 Matsha T, Brink L, van Rensburg S, Hon D, Lombard C, Erasmus R. Traditional home-brewed beer consumption and iron status in patients with esophageal cancer and healthy control subjects from Transkei, South Africa. Nutr Cancer, 2006, 56(1):67-73.
69 Memik F. Alcohol and esophageal cancer, is there an exaggerated accusation? Hepatogastroenterology, 2003, 50(54): 1953-5.
70 张东峰,许小幸,吕小翠,仇丽华.低出生体重影响因素的Logistic回归分析.中国公共卫生,2004,20(1):40-42.
71 Passos VM, Barreto SM, Diniz LM, Lima-Costa MF. Type 2 diabetes: prevalence and associated factors in a Brazilian community-the Bambui health and aging study. Sao Paulo Med J, 2005, 123(2): 66-71.
72 Yang CX, Wang HY, Wang ZM, Du HZ, Tao DM, Mu XY, Chen HG, Lei Y, Matsuo K, Tajima K. Risk factors for esophageal cancer: a case-control study in South-western China. Asian Pac J Cancer Prev, 2005, 6(1): 48-53.
73 Hashibe M, Boffetta P, Janout V, Zaridze D, Shangina O, Mates D, Szeszenia-Dabrowska N, Bencko V, Brennan P. Esophageal cancer in Central and Eastern Europe: tobacco and alcohol. Int J Cancer, 2007, 120(7): 1518-22.
74 余红平,施侣元,幺鸿雁.吸烟、饮酒与食管癌关系的Meta-分析.中国慢性病预防与控制,2003,11(1):1-2.
75 么鸿雁,陈辉,吕美霞,余红平,杨念念,方亚,段纪俊,施侣元.行为生活方式对恶性肿瘤发病影响的综合分析.中国公共卫生,2003,19(4):407-408.
76 Ji J, Hemminki K. Clin Gastroenterol Hepatol. Familial risk for esophageal cancer: an updated epidemiologic study from Sweden. Epub, 2006, 4(7):840-5.
77 Garavello W, Negri E, Talamini R, Levi F, Zambon P, Dal Maso L, Bosetti C, Franceschi S, La Vecchia C. Family history of cancer, its combination with smoking and drinking, and risk of squamous cell carcinoma of the esophagus. Cancer Epidemiol Biomarkers Prev, 2005, 14(6): 1390-3.
78 Wei WQ, Abnet CC, Lu N, Roth MJ, Wang GQ, Dye BA, Dong ZW, Taylor PR, Albert P, Qiao YL, Dawsey SM. Risk factors for oesophageal squamous dysplasia in adult inhabitants of a high risk region of China. Gut, 2005, 54(6): 759-63.
79 Wen D, Wang S, Zhang L, Zhang J, Wei L, Zhao X. Differences of Onset Age and Survival Rates in Esophageal Squamous Cell Carcinoma Cases with and without Family History of Upper Gastrointestinal Cancer from a High-incidence Area in North China. Fam Cancer, 2006, 5(4):343-52.
80 Mengesha B, Ergete W. Staple Ethiopian diet and cancer of the oesophagus. East Afr Med J, 2005, 82(7): 353-6.
81 Mayne ST, Risch HA, Dubrow R, Chow WH, Gammon MD, Vaughan TL, Borchardt L, Schoenberg JB, Stanford JL, West AB, Rotterdam H, Blot WJ, Fraumeni JF Jr. Carbonated soft drink consumption and risk of esophageal adenocarcinoma. J Natl Cancer Inst, 2006, 4; 98(1):72-5.
82 Isaacson C. The change of the staple diet of black South Africans from sorghum to maize (corn) is the cause of the epidemic of squamous carcinoma of the oesophagus. Med Hypotheses, 2005, 64(3): 658-60.
83 Zou XN, Taylor PR, Mark SD, Chao A, Wang W, Dawsey SM, Wu YP, Qiao YL, Zheng SF. Seasonal variation of food consumption and selected nutrient intake in Linxian, a high risk area for esophageal cancer in China. Int J Vitam Nutr Res, 2002, 72(6):375-82.
84 Lu H, Cai L, Mu LN, Lu QY, Zhao J, Cui Y, Sul JH, Zhou XF, Ding BG, Elashoff RM, Marshall J, Yu SZ, Jiang QW, Zhang ZF. Dietary mineral and trace element intake and squamous cell carcinoma of the esophagus in a Chinese population. Nutr Cancer, 2006, 55(1): 63-70.
85 Cai L, You NC, Lu H, Mu LN, Lu QY, Yu SZ, Le AD, Marshall J, Heber D, Zhang ZF. Dietary selenium intake, aldehyde dehydrogenase-2 and X-ray repair cross-complementing 1 genetic polymorphisms, and the risk of esophageal squamous cell carcinoma. Cancer, 2006, 106(11): 2345-54.
86 Hung HC, Huang MC, Lee JM, Wu DC, Hsu HK, Wu MT. Association between diet and esophageal cancer in Taiwan. J Gastroenterol Hepatol, 2004, 19(6): 632-7.
87 王凤荣;张祥宏;王俊灵;严霞;高建国;李绍森;孟凡书.河北省磁县农村农户储粮化学防霉效果观察.中华预防医学杂志,2001,35(2):90-92.
88 Hsia CC, Wu ZY, Li YS, Zhang F, Sun ZT. Nivalenol, a main Fusarium toxin in dietary foods from high-risk areas of cancer of esophagus and gastric cardia in China, induced benign and malignant tumors in mice, 2004, 12(2):449-56.
89 马吉祥,王勤忠,苏军英,李会庆.大豆异黄酮诱导人食管癌裸鼠移植瘤细胞凋亡.中国肿瘤,2004,13(1):34-37.
90 Sammon AM. Protease inhibitors and carcinoma of the esophagus. Cancer, 1998, 83(3):405-8.
91 Mayne ST, Risch HA, Dubrow R Chow WH, Gammon MD, Vaughan TL, Farrow DC, Schoenberg JB, Stanford JL, Ahsan H, West AB, Rotterdam H, Blot WJ, Fraumeni JF. Nutrient Intake and Risk of Subtypes of Esophageal and Gastric Cancer. Cancer Epidemiol Biomarkers Prev, 2001, 10(10): 1055-62.
92 邹小农,郑素芳,王雯,武燕萍,刘新伏,刘彬,王秀荣,范金虎,乔友林. 食管癌高发区林州市居民膳食营养状况调查.实用肿瘤杂志,2003,18(2):148-150.
93 张稳定,安丰山,林汉生,余华斐,陈少湖,王声.广东省揭阳市居民食管癌发病危险因素的病例对照研究.中华流行病学杂志,2001,22(6):442-445.
94 Palli D, Russo A, Ottini L, Masala G, Saieva C, Amorosi A, Cama A, D'Amico C, Falchetti M, Palmirotta R, Decarli A, Mariani Costantini R, Fraumeni JF Jr. Red meat, family history, and increased risk of gastric cancer with microsatellite instability. Cancer Res, 2001, 61(14):5415-9.
95 Levi F, Pasche C, Lucchini F, Bosetti C, La Vecchia C. Processed meat and the risk of selected digestive tract and laryngeal neoplasms in Switzerland. Ann Oncol, 2004, 15(2):346-9.
96 Wang JM, Xu B, Rao JY, Shen HB, Xue HC, Jiang QW. Diet habits, alcohol drinking, tobacco smoking, green tea drinking, and the risk of esophageal squamous cell carcinoma in the Chinese population. Eur J Gastroenterol Hepatol, 2007, 19(2): 171-6.
97 Gonzalez CA, Jakszyn P, Pera G, Agudo A, Bingham S, Palli D, Ferrari P, Boeing H, del Giudice G, Plebani M, Carneiro F; Nesi G, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H, Nyren O, Hallmans G, Martinez C, Dorronsoro M, Barricarte A, Navarro C, Quiros JR, Allen N, Key TJ, Day NE, Linseisen J, Nagel G, Bergmann MM, Overvad K, Jensen MK, Tjonneland A, Otsen A, Bueno-de-Mesquita HB, Ocke M, Peeters PH, Numans ME, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Psaltopoulou T, Roukos D, Lund E, Hemon B, Kaaks R, Norat T, Riboli E. Meat intake and risk of stomach and esophageal adenocarcinoma within the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst, 2006, 98(5): 345-54.
98 Howard BV, Manson JE, Stefanick ML, Beresford SA, Frank G, Jones B, Rodabough RJ, Snetselaar L, Thomson C, Tinker L, Vitolins M, Prentice R.. Low-fat dietary pattern and weight change over 7 years: the Women's Health Initiative Dietary Modification Trial. JAMA. 2006, Jan 4; 295(1):39-49.
99 Chainani-Wu N. Diet and oral, pharyngeal, and esophageal cancer. Nutr Cancer, 2002, 44(2): 104-26.
100 De Stefani E, Boffetta P, Deneo-Pellegrini H, Ronco AL, Correa P, Mendilaharsu M. The role of vegetable and fruit consumption in the aetiology of squamous cell carcinoma of the oesophagus: a case-control study in Uruguay. Int J Cancer, 2005, 116(1): 130-5.
101 王国清.降低食管癌发病率和死亡率的现场临术防治策略与方法。中华肿瘤杂志,1999,21(3):223.
102 Wang GQ, Abner CC, Shen Q, Lewin KJ, Sun XD, Roth MJ, Qiao YL, Mark SD, Dong ZW, Taylor. Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population. Gut, 2005, 54(2): 187-92.
103 Wu M, Zhao JK, Hu XS, Wang PH, Qin Y, Lu YC, Yang J, Liu AM, Wu DL, Zhang ZF, Frans KJ, van't Veer P. Association of smoking, alcohol drinking and dietary factors with esophageal cancer in high-and low-risk areas of Jiangsu Province, China. World J Gastroenterol, 2006, 12(11): 1686-93.
104 Dandara C, Li DP, Walther G, Parker MI. Gene-environment interaction: the role of SULT1A1 and CYP3A5 polymorphisms as risk modifiers for squamous cell carcinoma of the oesophagus. Carcinogenesis, 2006, 27(4):791-7.
105 Yang CX, Matsuo K, Ito H, Hirose K, Wakai K, Saito T, Shinoda M, Hatooka S, Mizutani K, Tajima K. Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and alcohol consumption: exploration of gene-environment and gene-gene interactions. Asian Pac J Cancer Prey, 2005, 6(3):256-62.
106 Sudo T, Mimori K, Nagahara H, Utsunomiya T, Fujita H, Tanaka Y, Shirouzu K, inoue H, Mori M. Identification of EGFR mutations in esophageal cancer. Eur J Surg Oncol, 2007, 33(1): 44-8.
107 Lord RV, O'Grady R, Sheehan C, Field AF, Ward RL. K-ras codon 12 mutations in Barrett's oesophagus and adenocarcinomas of the oesophagus and oesophagogastric junction. J Gastroenterol Hepatol, 2000, 15(7):730-6.
108 Sarbia M, Arjumand J, Wolter M, Reifenberger G, Heep H, Gabbert HE.Frequent c-myc amplification in high-grade dysplasia and adenocarcinoma in Barett esophagus. Am J Clin Pathol, 2001, 115(6): 835-840.
109 Raouf AA, Evoy DA, Carton E, Mulligan E, Griffin MM, Reynolds JV. Loss of Bcl—2 expression in Barett's dysplasia and adenocarcinoma is associated with tumor progression and worse survival but not with response to neoadjuvant chemoradiation. Dis Esophagus, 2003, 6(1): 17-23.
110 Ikeguchi M, Ueda T, Fukuda K, Yamaguchi K, Tsujitani S, Kaibara N. Expression of the murine double minute gene 2 oncoprotein in esophageal squamous cell carcinoma as a novel marker for lack of response to chemoradiotreatment. Am J Clin Oncol, 2002, 25(5): 454-459.
111 De Gottardi A, Dumonceau JM, Bruttin F, Vonlaufen A, Morard I, Spahr L,. Rubbia-Brandt L, Frossard JL, Dinjens WN, Rabinovitch PS, Hadengue A. Expression of the bile acid receptor FXR in Barrett's esophagus and enhancement of apoptosis by guggulsterone in vitro. Mol Cancer, 2006, 20(5):48.
112 Abdalla SI, Sanderson IR, Fitzgerald RC. Effect of inflammation on cyclooxygenase (COX)-2 expression in benign and malignant oesophageal cells. Carcinogenesis, 2005, 26(9): 1627-33.
113 黄克锋,李会庆.维生素D受体基因多态性与食管癌易感性关系.中国公共卫生,2006,22(9):1063-1064
114 Mulligan CJ, Robin RW, Osier MV, Sambuughin N, Goldfarb LG, Kitties RA, Hesselbrock D, Goldman D, Long JC. Allelic variation at alcohol metabolism genes (ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population. Human. Genetics, 2003, 113(4): 325-336.
115 Ishikawa H, Miyatsu Y, Kurihara K, Yokoyama K. Gene-environmental interactions between alcohol-drinking behavior and ALDH2 and CYP2E1 polymorphisms and their impact on micronuclei frequency in human lymphocytes. Mutat Res, 2006, 594(1-2): 1-9.
116 罗怀容,张亚平.乙醛脱氧酶2(ALDH2)基因研究进展及其与饮酒行为的关系.遗传,2004,26(2):263-266.
117 Wall TL. Genetic associations of alcohol and aldehyde dehydrogenase with alcohol dependence and their mechanisms of action. Therapeutic Drug Monitoring, 2005, 27(6):700-3.
118 Nishimura FT, Kimura Y, Abe S, Fukunaga T, Saijoh K. Effect of-361 ALDH2*1/ALDH2*2 polymorphism of aldehyde dehydrogenase-2 gene on alcohol metabolism and its expression in human peripheral blood leukocytes. Nihon Arukoru Yakubutsu Igakkai Zasshi, 2006 Apr; 41(2): 108-19.
119 Karamanakos PN, Pappas P, Stephanou P, Marselos M. Aldehyde dehydrogenase 2 activity affects symptoms produced by an intraperitoneal acetaldehyde injection, but not acetaldehyde lethality. J Toxicol Sci, 2005, 30(4):315-28.
120 Yamamoto K, Ueno Y, Mizoi Y, Tatsuno Y.. Genetic polymorphism of alcohol and aldehyde dehydrogenase and the effects on alcohol metabolism. Jpn J Alcohol & Drug Dependence, 1993, 28:13-25.
121 Ferguson RA, Goldberg DM. Genetic markers of alcohol abuse. Clin Chim Acta, 1997, 257:199-250.
122 Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, Inoue Y, Morita K, Takeda E, Pike JW. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol, 1997, 11 (8): 1165-79.
123 Cicek MS, Liu X, Schumacher FR, Casey G, Witte JS. Vitamin D receptor genotypes/haplotypes and prostate cancer risk. Cancer Epidemiol Biomarkers Prey, 2006, 15(12):2549-52.
124 Andersson P, Varenhorst E, Soderkvist R Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk. Eur J Cancer, 2006, 42(16):2833-7.
125 Pendas-Franco N, Gonzalez-Sancho JM, Suarez Y, Aguilera O, Steinmeyer A, Gamalto C, Berciano MT, Lafarga M, Munoz A. Vitamin D regulates the phenotype of human breast cancer cells. Differentiation, 2007, 75(3): 193-207.
126 de Lyra EC, da Silva IA, Katayama ML, Brentani MM, Nonogaki S, Goes JC, Folgueira MA. 25(OH)D3 and 1, 25(OH)2D3 serum concentration and breast tissue expression of lalpha-hydroxylase, 24-hydroxylase and Vitamin D receptor in women with and without breast cancer. J Steroid Biochem Mol Biol, 2006, 100(4-5): 184-92.
127 Gilad LA, Bresler T, Gnainsky J, Smirnoff P, Schwartz B. Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells. J Endocrinol, 2005, 185(3):577-92.
128 Palmer HG, Larriba MJ, Garcia JM, Ordonez-Moran P, Pena C, Peiro S, Puig I, Rodriguez R, de la Fuente R, Bernad A, Pollan M, Bonilla F, Gamallo C, de Herreros AG, Munoz A. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat Med, 2004, 10(9):917-9.
129 Wu CF, Wu DC, Hsu HK, Kao EL, Lee JM, Lin CC, Wu MT. Relationship between genetic polymorphisms of alcohol and aldehyde dehydrogenases and esophageal squamous cell carcinoma risk in males. World J Gastroenterol, 2005, 11 (33):5103-5108.
130 Kosugi S, Nishimaki T, Kanda T, Nakagawa S, Ohashi M, Hatakeyama K Clinical significance of serum carcinoembryonic antigen, carbohydrate antigen 19-9, and squamous cell carcinoma antigen levels in esophageal cancer patients. World J Surg, 2004, 28(7):680-5.
131 Hamada M, Naomoto Y, Shirakawa Y, Yamatsuji T, Noma K, Motoki T, Nobuhisa T, Okawa T, Haisa M, Gunduz M, Matsuoka J, Tanaka N. p53 expression and p21 expression are mutually exclusive in esophageal squamous cell carcinoma. Oncol Rep, 2004, 11(1):57-63.
132 Loges S, Clausen H, Reichelt U, Bubenheim M, Erbersdobler A, Schurr P, Yekebas E, Schuch G, Izbicki J, Pantel K, Bokemeyer C, Fiedler W.. Determination of microvessel density by quantitative real-time PCR in esophageal cancer: correlation with histologic methods, angiogenic growth factor expression, and lymph node metastasis. Clin Cancer Res, 2007, 13(1):76-80.
133 Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D. Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol, 2005, 15(4):297-310.
134 Chung YC, Hou YC, Chang CN, Hseu TH. Expression and prognostic significance of angiopoietin in colorectal carcinoma. J Surg Oncol, 2006, 94(7):631-638.
135 Quartarone E, Alonci A, Allegra A, Bellomo G, Calabro L, D'Angelo A, Del Fabro V, Grasso A, Cincotta M, Musolino C. Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies. Eur J Haematol, 2006, 77(6):480-5.
136 Lee OH, Fueyo J, Xu J, Yung WK, Lemoine MG, Lang FF, Bekele BN, Zhou X, Alonso MA, Aldape KD, Fuller GN, Gomez-Manzano C. Sustained angiopoietin-2 expression disrupts vessel formation and inhibits glioma growth. Neoplasia, 2006, 8(5):419-428.
137 Kebebew E, Peng M, Reiff E, Duh QY, Clark OH, McMillan A. Diagnostic and prognostic value of angiogenesis-modulating genes in malignant thyroid neoplasms. Surgery, 2005, 138(6): 1102-1110.
138 Zhang ZL, Liu ZS, Sun Q. Expression of angiopoietins, Tie2 and vascular endothelial growth factor in angiogenesis and progression of hepatocellular carcinoma. World J Gastroenterol, 2006, 12(26): 4241-4245.
139 Moon WS, Park HS, Yu KH, Jang KY, Kang MJ, Park H, Tarnawski AS Expression of angiopoietin 1, 2 and their common receptor Tie2 in human gastric carcinoma: implication for angiogenesis. J Korean Med Sci, 2006, 21(2): 272-278.
140 Wang J, Wu K, Zhang D, Tang H, Xie H, Hong L, Pan Y, Lan M, Hu S, Ning X, Fan D. Expressions and clinical significances of angiopoietin-1, -2 and Tie2 in human gastric cancer. Biochem Biophys Res Commun,2005,37(1):386-393.
141 Durkin AJ, Bloomston M, Yeatman TJ, Gilbert-Barness E, Cojita D, Rosemurgy AS, Zervos EE. Differential expression of the Tie-2 receptor and its ligands in human pancreatic tumors. J Am Coll Surg, 2004, 199(5):724-731.
142 张会娟,李建生,李道明,曹静,李海梅,庞霞,王永霞,赵志华.人食管鳞癌组织中促血管生成素-2的表达.郑州大学学报(医学版),2006,41(2):349-351.
143 孙秀菊,付浩,郑志红,王梅先,刘言厚。孙开来.Ang2基因表达与胃癌发生发展的关系.中国肿瘤临床 2003,30(8):536-539.
144 Nakayama T, Hatachi G, Wen CY, Yoshizaki A, Yamazumi K, Niino D, Sekine I. Expression and significance of Tie-1 and Tie-2 receptors, and angiopoietins-1, 2 and 4 in colorectal adenocarcinoma: Immunohistochemical analysis and correlation with clinicopathological factors. World J Gastroenterol 2005, 11(7): 964-969.
145 Sun XD, Liu XE, Wu JM, Cai XJ, Mou YP, Li JD. Expression and significance ofangiopoietin-2 in gastric cancer. World J Gastroenterol, 2004; 10(9): 1382-1385.
146 Shimoyama S, Yamasaki K, Kawahara M, Kaminishi M. Increased serum angiogenin concentration in colorectal cancer is correlated with cancer progression. Clinical Cancer Research, 1999, 5: 1125-1130.
147 Freestone B, Chong AY, Lim HS, Blann A, Lip GY. Angiogenic factors in atrial fibrillation: a possible role in thrombogenesis? Ann Med, 2005, 37(5): 365-372.
148 Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest, 2005, 115(8): 2108-2118.
1. Loges S, Clausen H, Reichelt U, Bubenheim M, Erbersdobler A, Schurr P, et al. Determination of microvessel density by quantitative real-time PCR in esophageal cancer: correlation with histologic methods, angiogenic growth factor expression, and lymph node metastasis. Clin Cancer Rcs 2007; 13(1):76-80. PMID: 17200341
2. Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D. Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 2005; 15(4):297-310. PMID: 16389942
3. Chung YC, Hou YC, Chang CN, Hseu TH. Expression and prognostic significance of angiopoietin in colorectal carcinoma. J Surg Oncol 2006; 94(7):631-638. PMID: 17066421
4. Bach F, Uddin FJ, Burke D. Angiopoietins in malignancy. Eur J Surg Oncol 2006; 5:Epub ahead of print. PMID: 16962282
5. Kuramoto H. Saito M, Watanabe J, Fujisawa T, Kamata Y, Nishimura Y, Arai T, et al. Angiopoietin-1, 2 and Tie2 expressions in endometrial adenocarcinoma—the Ang2 dominant balance up-regulates tumor angiogenesis in the presence of VEGF. Eur J Gynaecol Oncol 2006;27(2): 129-134. PMID: 16620053
6. Yu Q. The dynamic roles of angiopoietins in tumor angiogenesis. Future Oncol 2005;1(4):475-484. PMID: 16556024
7. Lee OH, Fueyo J, Xu J, Yung WK, Lemoine MG, Lang FF, et al. Sustained angiopoietin-2 expression disrupts vessel formation and inhibits glioma growth. Neoplasia 2006;8(5):419-428. PMID: 16790091
8. Kcbebew E, Peng M, Reiff E, Duh QY, Clark OH, McMillan A. Diagnostic and prognostic value of angiogenesis-modulating genes in malignant thyroid neoplasms. Surgery 2005;138(6): 1102-1110. PMID: 16360397
9. Zhang ZL, Liu ZS, Sun Q. Expression of angiopoietins, Tie2 and vascular endothelial growth factor in angiogenesis and progression of hepatocellular carcinoma. World J Gastroenterol 2006; 12(26):4241-4245. PMID: 16830384
10. Moon WS, Park HS, Yu KH, Jang KY, Kang M J, Park H, et al. Expression of angiopoietin 1, 2 and their common receptor Tie2 in human gastric carcinoma: implication for angiogenesis. J Korean Med Sci 2006;21(2):272-278. PMID: 16614513
11. Wang J, Wu K, Zhang D, Tang H, Xie H, Hong L, et al. Expressions and clinical significances of angiopoietin-1, -2 and Tie2 in human gastric cancer. Biochem Biophys Res Commun 2005;337(1):386-393. PMID: 16185665
12. Durkin AJ, Bloomston M, Yeatman TJ, Gilbert-Barness E, Cojita D, Rosemurgy AS, et al. Differential expression of the Tie-2 receptor and its ligands in human pancreatic tumors. J Am Coll Surg 2004;199(5):724-731. PMID: 15501112
13. Wang GQ, Wei WQ, Lu N, Hao CQ, Lin DM, Zhang HT, et al. Significance of screening by iodine staining of endoscopic examination in the area of high incidence of esophageal carcinoma. Ai Zheng 2003;22(2):175-177. PMID: 12600295
14. Wang GQ, Abnet CC, Shen Q, Lewin K J, Sun XD, Roth M J, et al. Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population. Gut 2005;54(2):187-192. PMID: 15647178
15. Zhang HJ, Li JS, Li DM, Cao J, Li HM, Pang X, et al. Expression of angiopoetin-2 in human esophageal squamous cell carcinoma tissue. J Zhengzhou Univ(Medical Sciences) 2006; 41 (2): 349-351.
16. Cancer Prevention and Treatment Office of the Health Ministry of China. Death investigation on malignant tumors in China. Beijing: People's Health Publishing House. 1979.
17. Zhao DL, Yang YD, Chen Mtt, Hu MX, Zhang QH, Guo XL, et al. Study on Risk Factors of Esophageal Cancer in Feicheng City. China J Cancer Prey Treat 2003;10 (1): 27-30.
18. Tew WP, Kelsen DR Ilson DH. Targeted therapies for esophageal cancer. Oncologist 2005;10(8):590-601. PMID: 16177283
19. Lepage C, Bouvier AM, Manfredi S, Coatmeur O, Cheynel N, Faivre J. Trends in incidence and management of esophageal adenocarcinoma in a well-defined population. Gastroenterol Clin Biol 2005;29(12): 1258-1263. PMID: 16518284
20. Dawsey SM, Fleischer DE, Wang GQ, Zhou B, Kidwell JA, Lu N, et al. Mucosal iodine staining improves endoscopic visualization of squamous dysplasia and squamous cell carcinoma of the esophagus in Linxian, China. Cancer 1998;83(2):220-231. PMID: 9669803
21. Wang GQ, Liu YY, Hao CQ, Lai SQ, Wang GQ, Lu N, et al. A comparative study of endoscopic image stained by iodine and histopathology in early esophageal cancer and precancerous lesions (dysplasia). Zhonghua Zhong Liu Za Zhi 2004;26(6):342-344. PMID: 15312343
22. Sun XJ, Fu H, Zheng ZH, Wang MX, Liu YH, Sun KL. Study on the correlation between expression of angiopoetin-2 (Ang-2) and carcinogenesis, progression of gastric cancer. Chinese Journal of Clinical Oncology 2003; 30 (8): 536-539.
23. Nakayama T, Hatachi G, Wen CY, Yoshizaki A, Yamazumi K, Niino D, et al. Expression and significance of Tie-1 and Tie-2 receptors, and angiopoietins-1, 2 and 4 in colorectal adenocarcinoma: Immunohistochemical analysis and correlation with clinicopathological factors. World J Gastroenterol 2005; 11(7):964-969. PMID: 15742397
24. Yamamoto Y, Takahashi M, Nishitani M, Kanayama HO, Kagawa S. Expression of angiopoietin-1 and -2, and its clinical significance in human bladder cancer. BJU Int 2005;95(4):660-663. PMID: 15705099
25. Sun XD, Liu XE, Wu JM, Cai XJ, Mou YP, Li JD. Expression and significance of angiopoietin-2 in gastric cancer. World J Gastroenterol. 2004;10(9):1382-1385. PMID: 15112366
26. Shouji S, Kazuki Y, Masaki K, Michio K. Increased serum angiogenin concentration in colorectal cancer is correlated with cancer progression. Clinical Cancer Research 1999; 5:1125-1130.
27. Freestone B, Chong AY, Lim HS, Blann A, Lip GY. Angiogenic factors in atrial fibrillation: a possible role in thrombogenesis?Ann Med 2005;37(5):365-372. PMID: 16179272
28. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, et al. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 2005; 115(8): 2108-2118. PMID: 16075055
29. Zhou YZ, Li H, Zhao DL, Li HQ. Multinomial logistic regression for the influencing factors of esophageal lesions. Chin J Public Health 2006; 22 (12):1437-1438.
1 Chitra S, Ashok L, Anand L, Srinivasan V, Jayanthi V. Risk factors for esophageal cancer in Coimbatore, southern India: a hospital-based case-control study. Indian J Gastroenterol, 2004, 23 (1): 19-21.
2 Garavello W, Negri E, Talamini R, Levi F, Zambon P, Dal Maso L, Bosetti C, Franceschi S, La Vecchia C. Family history of cancer, its combination with smoking and drinking, and risk of squamous cell carcinoma of the esophagus. Cancer Epidemiol Biomarkers Prey, 2005, 14(6): 1390-3.
3 Yokoyama A, Muramatsu T, Ohmori T, Higuchi S, Hayashida M, Ishii H. Esophageal cancer and aldehyde dehydrogenase-2 genotypes in Japanese males. Cancer Epidemiol Biomarkers Prey, 1996, 5(2):99-102. PMID: 8850269
4 Connie J. Mulligan, Robert W. Robin, Michael V. Osier, Nyamkhishig Sambuughin, Lev G. Goldfarb, Rick A. Kitties, Diane Hesselbrock, David Goldman and Jeffrey C. Long. Allelic variation at alcohol metabolism genes (ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population. Human Genetics, 2003, 113(4):
5 Yang CX, Matsuo K, Ito H, Hirose K, Wakai K, Saito T, Shinoda M, Hatooka S, Mizutani K, Tajima K. Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and alcohol consumption: exploration of gene-environment and gene-gene interactions, Asian Pac J Cancer Prev, 2005, 6(3):256-62. PMID: 16235983
6 Ishikawa H, Miyatsu Y, Kurihara K, Yokoyama K. Gene-environmental interactions between alcohol-drinking behavior and ALDH2 and CYP2E1 polymorphisms and their impact on micronuclei frequency in human lymphocytes. Mutat Res, 2006, 594(1-2):1-9. PMID: 16126235
7 Wall TL. Genetic associations of alcohol and aldehyde dehydrogenase with alcohol dependence and their mechanisms of action. Ther Drug Monit, 2005, 27(6):700-3. PMID: 16404797
8 Nishimura FT, Kimura Y, Abe S, Fukunaga T, Saijoh K. Effect of-361 ALDH2~*1/ALDH2~*2 polymorphism of aldehyde dehydrogenase-2 gene on alcohol metabolism and its expression in human peripheral blood leukocytes. Nihon Arukoru Yakubutsu Igakkai Zasshi, 2006, 41 (2): 108-19. PMID: 16734278
9 Isse T, Oyama T, Matsuno K, Uchiyama I, Kawamoto T. Aldehyde dehydrogenase 2 activity affects symptoms produced by an intraperitoneal acetaldehyde injection, but not acetaldehyde lethality. J Toxicol Sci, 2005, 30(4):315-28. PMID: 16404140
10 Yokoyama A, Kato H, Yokoyama T, Igaki H, Tsujinaka T, Muto M, Omori T, Kumagai Y, Yokoyama M, Watanabe H. Esophageal squamous cell carcinoma and aldehyde dehydrogenase-2 genotypes in Japanese females. Alcohol Clin Exp Res, 2006, 30(3):491-500. PMID: 16499490
11 Cai L, You NC, Lu H, Mu LN, Lu QY, Yu SZ, Le AD, Marshall J, Heber D, Zhang ZF. Dietary selenium intake, aldehyde dehydrogenase-2 and X-ray repair cross-complementing 1 genetic polymorphisms, and the risk of esophageal squamous cell carcinoma. Cancer, 2006, 106(11):2345-54. PMID: 16639733
12 Yokoyama A, Omori T, Tanaka Y, Yokoyama T, Sugiura H, Mizukami T, Matsushita S, Higuchi S, Maruyama K, Ishii H, Hibi T. p53 protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma. Cancer Lett, 2007, 247(2):243-52. PMID: 16759795
13 Chen Zhifeng Wang Guoqing Hou Jun, et al. Follow-up Results of Esophageal Squamous Severe Dysplasia in 158 cases. Chinese Journal of Clinical Oncology,, 2004, 31(6): 306-308
14 Asakage T, Yokoyama A, Haneda T, Yamazaki M, Muto M, Yokoyama T, Kato H, Igaki H, Tsujinaka T, Kumagai Y, Yokoyama M, Omori T, Watanabe H. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and drinking, smoking, and diet in Japanese men with oral and pharyngeal squamous cell carcinoma. Carcinogenesis, [Epub ahead of print] PMID: 17071628
15 WANG Guo-qing, LIU Yna-yuan, HAO Chang-qing, Shao-qing, WANG Gui—qi, LU Ning, YAN G Ling. A comparative study of endoscopic image stained by iodine and histopathology in early esophageal cancer and precancerous lesions (dysplasia). Chinese Journal of Oncology, 2004, 26 (6): 342-344.
16 WANG Guo qing, HAO Chang—qing, LAI Shao qing, et al. Endoscopic screening of esaphagea cancer with iodine staning in hjgh risked area. Chin J Dig Endosc, 2003, 20(6):377-379.
17 Office of Cancer Prevention and Treatment of China Health Ministry. Investigation on deaths of malignant tumors. Bijing: People's Medical Publishing House. 1979.
18 Yang CX, Wang HY, Wang ZM, Du HZ, Tao DM, Mu XY, Chen HG, Lei Y, Matsuo K, Tajima K. Risk factors for esophageal cancer: a case-control study in South-western China. Asian Pac J Cancer Prev, 2005, 6(1):48-53.
19 Xibib S, Meilan H, Moiler H, et al. Risk factors for oesophageal cancer in Linzhou, China: a case-control study. Asian Pac J Cancer Prev, 2003, 4(2): 119-24.
20 Lewis S J, Smith GD. Alcohol, ALDH2, and esophageal cancer: a meta-analysis v, hich illustrates the potentials and limitations of a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev, 2005, 14(8):1967-71. PMID: 16103445
21 Ogawa M, Oyama T, Isse T, Saito K, Tomigahara Y, Endo Y, Kawamoto T. A comparison of covalent binding of ethanol metabolites to DNA according to Aldh2 genotype. Toxicol Lett, 2007, 168(2): 148-54. PMID: 17166675
22 Ishikawa H, Ishikawa T, Yamamoto H, Fukao A, Yokoyama K. Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms. Mutat Res, 2007, 615(1-2): 134-42. PMID: 17207821
23 Wu CF, Wu DC, Hsu HK, Kao EL, Lee JM, Lin CC, Wu MT. Relationship between genetic polymorphisms of alcohol and aldehyde dehydrogenases and esophageal squamous cell carcinoma risk in males. World J Gastroenterol, 2005, 11(33):5103-8. PMID: 16127737
24 Muramatsu, T.; Zu-Cheng, W.; Yi-Ru, F.; Kou-Bao, H.; Heqin, Y.; Yamada, K.; Higuchi, S.; Harada, S.; Kono, H. Alcohol and aldehyde dehydrogenase genotypes and drinking behavior of Chinese living in Shanghai. Hum Genet, 1995, 96:151-154,. PubMed ID: 7635462
25 Yokoyama A, Kato H, Yokoyama T, Tsujinaka T, Muto M, Omori T, Haneda T, Kumagai Y, Igaki H, Yokoyama M, Watanabe H, Fukuda H, Yoshimizu H. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma. Carcinogenesis, 2002, 23 (11): 1851-9. PMID: 12419833
26 Chen YJ, Chen C, Wu DC, Lee CH, Wu CI, Lee JM, Goan YG, Huang SP, Lin CC, Li TC, Chou YP, Wu MT. Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisms on esophageal cancer risks. Int J Cancer, 2006, 119(12):2827-31. PMID: 17036331
27 Yamada Y, Imai T, Ishizaki M, Honda R. ALDH2 and CYP2E 1 genotypes, urinary acetaldehyde excretion and the health consequences in moderate alcohol consumers. J Hum Genet, 2006;51(2):104-11. PMID: 16365683