毒物代谢酶基因多态性与胃癌遗传易感性的分子流行病学研究
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摘要
虽然胃癌的发病率在全球呈普遍下降的趋势，但世界仍以年新发
病例数755，000例（占世界各种癌症病例总数的9.9％）而位居恶
性肿瘤发病的第二位，因胃癌而死亡的病例数占全部癌症死亡人数的
1/4左右。在我国，胃癌死亡率居各种恶性肿瘤之首，而江苏省是全
国胃癌高发区之—，胃癌死亡率为33.32/10万，严重危害着人民的生
命和健康。因此，深入进行胃癌病因学研究，积极采取有效的预防控
制措施成了当务之急。为此，本课题在江苏省两个胃癌高发区（金坛
市和淮安市）开展了以人群为基础的分子流行病学研究。
第一部分 细胞色素P4502E1基因多态性与胃癌遗传
易感性关系的探讨
胃癌的发生是一个多因素多步骤的过程，其中食物来源的N-亚硝
基化合物与胃癌之间的联系最受人们的重视。细胞色素
P4502E1（CYP2E1）是人体代谢亚硝胺的重要同功酶，本研究应用聚合
酶链反应和限制性片段长度多态性（PCR-RFLP）技术对CYP2E1 Rsa
Ⅰ位点的多态性与胃癌易感性间的关系进行了探讨。主要结果如下：
1.CYP2E1 RsaⅠ识别位点基因型和等位基因的分布
CYP2E1各基因型在胃癌病例中的分布频率分别为A（纯合子野生
型c1/c1）型71.1％、B（杂合子型c1/c2）型24.4％、C（纯合子突变型c2/c2）
型4.4％，在对照组中的分布频率分别为A（纯合子野生型c1/c1）型
52.2％、B（杂合子型c1/c2）型43.3％、C（纯合子突变型c2/c2）型4.4％，
各基因型在胃癌病例和对照中的分布有显著性差异（x~2=7.34，df=2，
P=0.025）；病例组CYP2E1基因型为A型的频率显著高于对照，将B
基因型与C基因型合并计算OR值为OR=2.42（95％CI=1.19～5.01），
南京医科大学硕士学位论文D
A基因型是胃癌的易感基因型；＊猢因在病例组中的肺频率D
（83．3o／o）显著高于对照组（7．9％e．77，P＝0．028）。
2．CYPZEI基固多态与撰卜J淹菜、蔬菜取夫卜作用对胃癌的影响 D
携有CYPZEI A（iil，－－子野生型CI／cl）型基因者若经常摄入胳菜，7
则患胃癌的危险防是携有 CThZEI非 A型（杂合子 B沁 l／c2）型或纯合 D
子突变型 C…）型倦因者H少摄入胳菜个体的 3．89 W95％CI为 D
1．56－9刀）；CYPZEI A（f：l｝fA子野生型CI／cl）基因型且少摄入新鲜蔬 7
菜的个体患胃癌的危险眼CYPZEI 非A型（杂合子Bk1／c2）型或纯 D
合子突变型qCZ／c2）型）H多摄入新鲜蔬菜怵的5．50倍O5OCI为
2．08－14．5Q；CYPZEI基因多态性与饮食因素对胄癌的发生姊协同 7
作用。D
3．不同种族yJ薛CYPZEI Rsa 位点多态性的比较7
D CYPZEI ha ＠o位点多态性姊明显的种族差异。我国江苏地 D
D 区汉族人群以A（iil｝f子野生型dl／cl倦因型为主O2．2％），其次为B（杂D
合子型 CI／cZ）型（4．3o／0），C纯合子突变型 cZicZ）型分布频率最低’
＊．4％）；等跑因CI、CZ M频率分别为73．9％和26．1汰与其他种族
卜 比较，我国基因型和等振因肺频率与日本人群的拥糊目近，
牡CI／cl）基因型和CI等位基因频率明显低于欧美懈。
I 器二鄙分GSTMI、GSTTI基因型与胃癌遗传
D 一多态性与腑的活化雕能力的帅差异有关，靴
甘肽转硫闽GSTs）的缺乏，可能影响对某些化学物质的a解毒过
D 程，从而增加怵的患癌风险，例究结蛐不一致。本文运用多聚
酪啼钉之应①CRM就GSTMI、GSTTI基因型与胃癌跳易感。铁的
D 关系断了进一步邯。烘结果如下：
l－2．
D 南京医科大学硕士学位论文
l．GSTMI、GSTTIg白基因型在病例、对照的分布
D 胃癌病例GSTMI空白基因型频率为57．8％，高于对照组＊．l％）
】但差异无显著性（OR＝l．29，95％CM＊0－2．36；x－ru．81，P＝0．3691）；
D 胃癌病例GSThl空白基因型频率为60．0％，显著高于对照组（4．3o／o）
D 灯乙5．01，Ph．025＼GSTTI基因缺失增加胃癌发生的危险性PR7
J．83，95％CI为 1＊0—3．39）。
DZ．基④肤合作川对8＄及生的彭悯
］某因联今作用分折表明，GSTMI与GSThlM基W鄙炙芹夭的／i’’tx
D 患胃癌的危险性是两基因都存在个体的3．04倍汐50CI为1．23－
7．531；叫目酶CYPZEI 基因为A型叫酶GSTMI 基因缺失的个
】体；sg癌的危险赃CYPZEI 基因非A型且GSTMI基囚存在个体
的3．17倍O5％CI为1．28－7．83）；＋B酶CYPZEI基因为A型且二下R
D 酶GSTTI基因缺失的个?
Although gastric cancer (GC) is declining in frequency in the world, its
new cases still ranks second ( 755 000 per year), comprising 9.9% of all
new malignant cases. GC is responsible for a fourth of all malignant death.
In China, GC is the leading cause of cancer death. Jiangsu Province is one
of the highest-risk areas of CC in our countiy, with the mortality rate is
33.32 per 100 000. It causes great harm to people’s health and life. So it is
urgent to find out GC etiology and take effective prevention measures. To
reach this target, a population-based molecular epidemiological study on
CC was conducted in the two high-risk areas (Jintan and Huai’an County)
of Jiangsu Province.
Part I The Relationship between Genetic Polymorphism of
Cytochrome P450 (CYP2E1) and Susceptibility to
Gastric Cancer
There are considerable evidences suggesting that human CC is a
multistage process with multiple risk factors. Within them, N-nitroso
compounds from dietary sources are involved in CC. CYP2E1 is a critical
isozyme in metabolizing N-nitrosamines. To explore the association
between genetic polymorphism of CYP2E 1 digested by restriction
enzyme Rsa I and susceptibility to CC, a 1: 1 matched case-control
study was conducted. Genotyping of CYP2E1 was performed using
PCR-based RFLP analysis on DNA isolated from peripheral white blood
cells from ninety patients with primary CC and ninety control subjects
matched according to age, sex, nationality and residential area.
1. Frequencies of CYP2E1 genotype and allele
There were three genotypes of CYP2E1 resulting from digestion with
restriction enzyme Rsa I type A, a wild-type homozygote cl/cl; type B,
the heterozygote cl/c2; and type C, a mutant type homozygote c2/c2. In
cases, the frequencies of A (cl/cl) genotype, B (cl/c2) genotype and
C(c2/c2) are 71.1%, 24.4% and 4.4% respectively. In controls, the
frequencies of A (cl/cl) genotype, B (cl/c2) genotype and C(c2/c2) are
52.2%, 43.3% and 4.4% respectively. There is a significant difference in
the frequencies ofA(cl/ci), B(clIc2), C(c2/c2) genotypes( 7.34, df2,
P=0.025) between cases and controls. Patients with CC were more likely
to be homozygous for the Rsa I genotype cl/cl than controls. The odds
ratio of GC for the cl/cl genotype compared with two other genotypes
combined was 2.42(95%CN4 . l95.0 1). The frequencies of allele ci and
c2 in cases were significantly different from those in controls(X24.77,
P=0.028) with the frequencies of allele ci in cases and controls being
83.3% and 16.7% respectively and c2 in cases and controls 73.9% and
26.1% respectively. CYP2E1 is a genetic susceptibility factor involved in
the GC carcinogenesis.
2. The combined effect between genetic polymorphism of CYP2E1 and
pickle, vegetables on CC
Subjects who had A(c 1/cl) genotype of CYP2E1 and ate pickle
frequently had 3.89(95%CJ=l.56 s 9.71) folds risk developing CC
compared with those who had B(cl/c2) genotype or C(c2/c2) genotype of
CYP2E1 and seldom ate pickle. Individuals exposed to A(cl/ci) genotype
of CYP2E1 and low intake of vegetables had 5.50(95%CI=2.08拁?4.56)
folds risk developing CC compared with those who had B(ci/c2)
genotype or C(c2/c2) genotype of CYP2E1 and high intake of vegetables.
There lies synergy between genetic polymorphism of CYP2E1 and dietary
factors on CC.
3. Comparison of CYP2E 1 gene polymorphism in different races
The A(cl/cl) genotype of
病例数755，000例（占世界各种癌症病例总数的9.9％）而位居恶
性肿瘤发病的第二位，因胃癌而死亡的病例数占全部癌症死亡人数的
1/4左右。在我国，胃癌死亡率居各种恶性肿瘤之首，而江苏省是全
国胃癌高发区之—，胃癌死亡率为33.32/10万，严重危害着人民的生
命和健康。因此，深入进行胃癌病因学研究，积极采取有效的预防控
制措施成了当务之急。为此，本课题在江苏省两个胃癌高发区（金坛
市和淮安市）开展了以人群为基础的分子流行病学研究。
第一部分 细胞色素P4502E1基因多态性与胃癌遗传
易感性关系的探讨
胃癌的发生是一个多因素多步骤的过程，其中食物来源的N-亚硝
基化合物与胃癌之间的联系最受人们的重视。细胞色素
P4502E1（CYP2E1）是人体代谢亚硝胺的重要同功酶，本研究应用聚合
酶链反应和限制性片段长度多态性（PCR-RFLP）技术对CYP2E1 Rsa
Ⅰ位点的多态性与胃癌易感性间的关系进行了探讨。主要结果如下：
1.CYP2E1 RsaⅠ识别位点基因型和等位基因的分布
CYP2E1各基因型在胃癌病例中的分布频率分别为A（纯合子野生
型c1/c1）型71.1％、B（杂合子型c1/c2）型24.4％、C（纯合子突变型c2/c2）
型4.4％，在对照组中的分布频率分别为A（纯合子野生型c1/c1）型
52.2％、B（杂合子型c1/c2）型43.3％、C（纯合子突变型c2/c2）型4.4％，
各基因型在胃癌病例和对照中的分布有显著性差异（x~2=7.34，df=2，
P=0.025）；病例组CYP2E1基因型为A型的频率显著高于对照，将B
基因型与C基因型合并计算OR值为OR=2.42（95％CI=1.19～5.01），
南京医科大学硕士学位论文D
A基因型是胃癌的易感基因型；＊猢因在病例组中的肺频率D
（83．3o／o）显著高于对照组（7．9％e．77，P＝0．028）。
2．CYPZEI基固多态与撰卜J淹菜、蔬菜取夫卜作用对胃癌的影响 D
携有CYPZEI A（iil，－－子野生型CI／cl）型基因者若经常摄入胳菜，7
则患胃癌的危险防是携有 CThZEI非 A型（杂合子 B沁 l／c2）型或纯合 D
子突变型 C…）型倦因者H少摄入胳菜个体的 3．89 W95％CI为 D
1．56－9刀）；CYPZEI A（f：l｝fA子野生型CI／cl）基因型且少摄入新鲜蔬 7
菜的个体患胃癌的危险眼CYPZEI 非A型（杂合子Bk1／c2）型或纯 D
合子突变型qCZ／c2）型）H多摄入新鲜蔬菜怵的5．50倍O5OCI为
2．08－14．5Q；CYPZEI基因多态性与饮食因素对胄癌的发生姊协同 7
作用。D
3．不同种族yJ薛CYPZEI Rsa 位点多态性的比较7
D CYPZEI ha ＠o位点多态性姊明显的种族差异。我国江苏地 D
D 区汉族人群以A（iil｝f子野生型dl／cl倦因型为主O2．2％），其次为B（杂D
合子型 CI／cZ）型（4．3o／0），C纯合子突变型 cZicZ）型分布频率最低’
＊．4％）；等跑因CI、CZ M频率分别为73．9％和26．1汰与其他种族
卜 比较，我国基因型和等振因肺频率与日本人群的拥糊目近，
牡CI／cl）基因型和CI等位基因频率明显低于欧美懈。
I 器二鄙分GSTMI、GSTTI基因型与胃癌遗传
D 一多态性与腑的活化雕能力的帅差异有关，靴
甘肽转硫闽GSTs）的缺乏，可能影响对某些化学物质的a解毒过
D 程，从而增加怵的患癌风险，例究结蛐不一致。本文运用多聚
酪啼钉之应①CRM就GSTMI、GSTTI基因型与胃癌跳易感。铁的
D 关系断了进一步邯。烘结果如下：
l－2．
D 南京医科大学硕士学位论文
l．GSTMI、GSTTIg白基因型在病例、对照的分布
D 胃癌病例GSTMI空白基因型频率为57．8％，高于对照组＊．l％）
】但差异无显著性（OR＝l．29，95％CM＊0－2．36；x－ru．81，P＝0．3691）；
D 胃癌病例GSThl空白基因型频率为60．0％，显著高于对照组（4．3o／o）
D 灯乙5．01，Ph．025＼GSTTI基因缺失增加胃癌发生的危险性PR7
J．83，95％CI为 1＊0—3．39）。
DZ．基④肤合作川对8＄及生的彭悯
］某因联今作用分折表明，GSTMI与GSThlM基W鄙炙芹夭的／i’’tx
D 患胃癌的危险性是两基因都存在个体的3．04倍汐50CI为1．23－
7．531；叫目酶CYPZEI 基因为A型叫酶GSTMI 基因缺失的个
】体；sg癌的危险赃CYPZEI 基因非A型且GSTMI基囚存在个体
的3．17倍O5％CI为1．28－7．83）；＋B酶CYPZEI基因为A型且二下R
D 酶GSTTI基因缺失的个?
Although gastric cancer (GC) is declining in frequency in the world, its
new cases still ranks second ( 755 000 per year), comprising 9.9% of all
new malignant cases. GC is responsible for a fourth of all malignant death.
In China, GC is the leading cause of cancer death. Jiangsu Province is one
of the highest-risk areas of CC in our countiy, with the mortality rate is
33.32 per 100 000. It causes great harm to people’s health and life. So it is
urgent to find out GC etiology and take effective prevention measures. To
reach this target, a population-based molecular epidemiological study on
CC was conducted in the two high-risk areas (Jintan and Huai’an County)
of Jiangsu Province.
Part I The Relationship between Genetic Polymorphism of
Cytochrome P450 (CYP2E1) and Susceptibility to
Gastric Cancer
There are considerable evidences suggesting that human CC is a
multistage process with multiple risk factors. Within them, N-nitroso
compounds from dietary sources are involved in CC. CYP2E1 is a critical
isozyme in metabolizing N-nitrosamines. To explore the association
between genetic polymorphism of CYP2E 1 digested by restriction
enzyme Rsa I and susceptibility to CC, a 1: 1 matched case-control
study was conducted. Genotyping of CYP2E1 was performed using
PCR-based RFLP analysis on DNA isolated from peripheral white blood
cells from ninety patients with primary CC and ninety control subjects
matched according to age, sex, nationality and residential area.
1. Frequencies of CYP2E1 genotype and allele
There were three genotypes of CYP2E1 resulting from digestion with
restriction enzyme Rsa I type A, a wild-type homozygote cl/cl; type B,
the heterozygote cl/c2; and type C, a mutant type homozygote c2/c2. In
cases, the frequencies of A (cl/cl) genotype, B (cl/c2) genotype and
C(c2/c2) are 71.1%, 24.4% and 4.4% respectively. In controls, the
frequencies of A (cl/cl) genotype, B (cl/c2) genotype and C(c2/c2) are
52.2%, 43.3% and 4.4% respectively. There is a significant difference in
the frequencies ofA(cl/ci), B(clIc2), C(c2/c2) genotypes( 7.34, df2,
P=0.025) between cases and controls. Patients with CC were more likely
to be homozygous for the Rsa I genotype cl/cl than controls. The odds
ratio of GC for the cl/cl genotype compared with two other genotypes
combined was 2.42(95%CN4 . l95.0 1). The frequencies of allele ci and
c2 in cases were significantly different from those in controls(X24.77,
P=0.028) with the frequencies of allele ci in cases and controls being
83.3% and 16.7% respectively and c2 in cases and controls 73.9% and
26.1% respectively. CYP2E1 is a genetic susceptibility factor involved in
the GC carcinogenesis.
2. The combined effect between genetic polymorphism of CYP2E1 and
pickle, vegetables on CC
Subjects who had A(c 1/cl) genotype of CYP2E1 and ate pickle
frequently had 3.89(95%CJ=l.56 s 9.71) folds risk developing CC
compared with those who had B(cl/c2) genotype or C(c2/c2) genotype of
CYP2E1 and seldom ate pickle. Individuals exposed to A(cl/ci) genotype
of CYP2E1 and low intake of vegetables had 5.50(95%CI=2.08拁?4.56)
folds risk developing CC compared with those who had B(ci/c2)
genotype or C(c2/c2) genotype of CYP2E1 and high intake of vegetables.
There lies synergy between genetic polymorphism of CYP2E1 and dietary
factors on CC.
3. Comparison of CYP2E 1 gene polymorphism in different races
The A(cl/cl) genotype of
引文
1. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer, 1993, 54:594-606.
2．李连弟，鲁凤珠，张思维等．1990～1992年中国恶性肿瘤死亡流行分布情况分析．中华肿瘤杂志，1996，18(6)：403-407．
3．卜绍唐，熊宗幡．江苏省人口全死因研究．南京：东南大学出版社，1996．
4．潘凤娣．金坛市恶性肿瘤死亡动态特点研究．中国公共卫生，1999，15(2)：114-115．
5．王彬，陈瑾．徐天亮．肿瘤高发区江苏淮安1982～1996年主要恶性肿瘤死亡动态分析．肿瘤，1999，19(6)：361-362．
6．耿贯一主编．流行病学(第三卷)．第二版．北京：人民卫生出版社，1998：210-238．
7．薛开先．细胞色素P450多态及其在肿瘤易感性和突变中的进展．癌变，畸变，突变，1997，9(4)：256-259．
8. Gonzales FJ, Gelboin HV, Human cytochromes P450: evolution and cDNA-directed expression. Environmental Health Perspectives,1992,98:81-85.
9. Kato S, Peter GS, Neil EC, et al. Cytochrome P450 ⅡE1 genetic polymorphisms, racial variation, and lung cancer risk. Cancer Res,1992,52: 6712-6715.
10．林东昕，唐永明，彭琼等．细胞色素P4502E1和谷胱甘肽转硫酶P1基因与食管癌易患性．中华肿瘤杂志，1998，20(2)：94-97．
11. Yu MW, Alicja GY, Sinnabhatr C, et al. Cytochrome P4502E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology, 1995,109:1266-1273.
12. London SJ, Daly AK, Cooper J, et al. Lung cancer risk in relation to the CYP2E1 Rsa I genetic polymorphism among African-Americans and Caucasians in Los Angeles county. Pharmacogenetics, 1996,6:151-158.
13．沈洪兵．2型糖尿病的流行病学及高危险人群筛检方法研究．上海医科大学博士研究生毕业论文，1999．
14. Hirvonen A, Kirsti HP, Sisko A, et al. The human CYP2E1 gene and lung cancer: Dra I and Rsa I restriction fragment length polymorphisms in a Finnish study population. Carcinogenesis, 1993,14(1):85-88.
15. Tsutsumi M, Takada A, Wang JS. Genetic polymorphisms of cytochrome P4502E1 related to the development of alcoholic liver disease. Gastroenterology, 1994,107:1430-1435.
16. Hayashi S, Watanabe J, Kawajiri K. Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P4502E1 gene. J Biochem, 1991,110:559-565.
17．贺智敏，陈主初．CYP2E1基因及其多态性与化学致癌易感性．国外医学病理科学与临床分册，1998，18(4)：292-294．
18. Uematsu F, Ikawa S, Kikuchi H, et al. Restriction fragment length polymorphism of the human CYP2E1(cytochrome P450 ⅡE1) gene and susceptibility to lung cancer: possible relevance to low smoking exposure. Pharmacogenetics, 1994,4:58-63.
19. Maezawa Y, Masayoshi Y, Gotaro T Association between restriction fragment length polymorphism of the human cytochrome P450 Ⅱ E1 gene and susceptibility to alcoholic liver cirrhosis. The American J of Gastroenterology, 1994,89(4): 561-565.
20．王立东，刑莹，周琦．大鼠食管上皮细胞色素P4502E1和谷胱甘肽S-转移酶的初步研究．河南医科大学学报，1995，30(2)：132-134．
21．楚建军，徐耀初，叶本法等．消化道肿瘤高发区腌菜N-亚硝基化合物含量及致突变作用．中华预防医学杂志，1994，28(4)：202-205．
22. Correa E Human gastric carcinogenesis: a multistep and multifactorial process-first American Cancer Society Award Lecture on epidemiology and prevention. Cancer Res, 1992,52:6735-6740.
23. Awasthi YC, Sharma R, Singhalss. Human glutathione S-transferase. Int J Biochem, 1994,26:295-308.
24. Seidegard J, Pero RW, Miller DG, et al. A glutathione transferase in human leukocytes as a marker for the susceptibility to lung cancer. Carcinogenesis, 1986,7:751-753.
25. Valle NS, Motulsky AG, Eaton DL, et al. The glutathione S-transferase polymorphism as a marker for susceptibility to lung carcinoma. Cancer Res, 1993,53:2313-2318.
26．边建超，王金兵，吴燕等．GSTM1空白基因型与原发性肝细胞癌遗传易感性的研究．中华医学遗传学杂志，1996，13(6)：353-356．
27. Bell DA, Talor JA, Paulson DF, et al. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1(GSTM1) that increase susceptibility to bladder cancer. J Natl Cancer Inst, 1993,85(14): 1159-1164.
28. Brockmoeller J, Kerb R, Drakoulis N, et al. Glutathione S-transferase M1 and its variants A and B as host factors of bladder cancer susceptibility: a case-control study. Cancer Res, 1994,54:4103-4111.
29. Zhong S, Wyllie AH, Wolf CR. et al. Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis, 1993,14(9): 1821-1824.
30. Sato M, Sato I, Izumo T, et al. Genetic polymorphism of drug-metabolizing enzymes and susceptibility to oral cancer. Carcinogenesis, 1999,20(10): 1927-1931.
31. Board PG. Biochemical genetics of glutathione S-transferase in man. Am J Hum Genet, 1980,33:36-43.
32. Warholm M, Guthenberg C, Mannervik B. Molecular and catalytic properties of glutathione transferase μfrom human liver: an enzyme efficiently conjugating epoxides. Biochemistry,1983,22:3610-3617.
33. Wiencke JK, Pemble S, Ketterer B, et al. Gene deletion of glutathione transferase theta 1: Correlation with induced genetic damage and potential role in endogenous mutagenesis. Cancer Epid Biomarkers Prev, 1995,4:253-260.
34. Pemble S, Schroeder KR, Spencer SR, et al. Human glutathione S-transferase theta(GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J,1994,300:271-276.
35. Pearson WR, Vorachek WR, Xu SJ, et al. Identification of class-mu glutathione transferase genes GSTM1-GSTM5 on human chromosome lp13. Am J Hum Genet, 1993,53(1):220-233.
36. Lin HJ, Han CY, Bemstein DA, et al. Ethnic distribution of the glutathione transferase Mu 1-1 (GSTM1) null genotye in 1473 individuals and application to bladder cancer susceptibility. Carcinogenesis, 1994,15(5): 1077-1081.
37. Deakin M, James E, Charles H, et al. Glutathione S-transferase GSTT1 genotypes and susceptibility to cancer: studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers. Carcinogenesis,1996,17(4):881-884.
38．蔡琳，俞顺章，陈建顺．谷胱甘肽转硫酶M1、T1基因型与胃癌易感性的关系．中华预防医学杂志，1999，33(6)：331-333．
39．潘凯枫，吕有勇，谭文等．谷胱甘肽转硫酶M1和T1基因缺失与胃癌风险．中华预防医学杂志，1999，33(Suppl)：24-26．
40. Warholm M, Rane A, Alexandrie A, et al. Genotypic and phenotypic determination of polymorphic glutathione transferase T1 in a Swedish population. Pharmacogenetics, 1995,5:252-254.
41. Chenevix-Trench G, Young J, Coggan M, et al. Glutathione S-transferase M1 and T1 polymorphisms: susceptibility to colon cancer and age of onset. Carcinogenesis,1995,16:1655-1657.
42. Elexpuru-Camiruaga J, Buxton N, Kandula V, et al. Susceptibility to astrocytoma and meningioma: influence of allelism at glutathione S-transferase (GSTT1 and GSTM1) and cytochrome P-450(CYP2D6) loci. Cancer Res, 1995,55:4237-4239.
43. Nelson HH, Wiencke JK, Christiani DC, et al. Ethnic differences in the prevalence of the homozygous deleted genotype of glutathione S-transferase theta. Carcinogenesis, 1995,16:1243-1245.
44. Katon T, Naoki N, Yusuke K, et al. Glutathione S-transferase M1(GSTM1) and T1(GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis, 1996,17(9): 1855-1859.
45. Jourenkova-Mironova N, Voho A, Bouchardy C, et al. Glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes and the risk of smoking-related oral and pharyngeal cancers. Int J Cancer, 1999,81(1):44-48.
46. Setiawan VW, Zhang ZF, Yu GP, et al. GSTT1 and GSTM1 null genotypes and the risk of gastric cancer: a case-control study in a Chinese population. Cancer-Epidemiol-Biomarkers-Prev,2000,9(1):73-80.
47. Smith CAD, Smith G, Wolf CR, et al. Genetic polymorphisms in xenobiotic metabolism. Eur J Cancer, 1994,30A: 1935-1941.
48. Brockmoller J, Kerb R, Drakoulis N, et al. Genotype and phenotype of glutathione S-transferase class μ isoenzyme μ and ψ in lung cancer patients and controls. Cancer Res, 1993,53(5):1004-1011.
49. Walker AM. Proportion of disease attributable to the combined effect of two factors. Int J Epidemiol, 1981,10:81-85.
50．戴文灿，王声涌，陈英等．病因分值在病例对照研究中的应用—肺癌危险因素的交互效应．中华流行病学杂志，1997，18(6)：341-344．
51. Nebert DW. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet, 1997,60:265-271.
52. Genetic polymorphism of CYF2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias. Carcinogenesis, 1999,20(7): 1225-1229.
53. Inoue M, Tajima K, Yamamura Y, et al. Family history and subsite of gastric cancer: Data from a case-referent study in Japan. Int J Cancer, 1998,76:801-805.
54. Bartsch H, Montesano R. Relevance of nitrosamines to human cancer. Carcinogenesis(Lond.), 1984,5(1381-1393).
55. Lu SH, Ohshima H, Fu HM, et al. Urinary excretion of N-nitrosamino acids and nitrate by inhabitants of high-and low-risk areas for esophageal cancer in northern China: endogenous formation of nitrosoproline and its inhibition by vitamin C. Cancer Res, 1986,46:1485-1491.
56．陈君石，闻芝梅主译．食物、营养与癌症预防．上海：上海医科大学出版社，1999：152-185．
57．季川，李铭新．林县酸菜在食管癌病因中作用的研究：Ⅱ酸菜中亚硝胺及其前体物的检测．中国医学科学院学报，1991，13：230-232．
58. Yu GP, Hsieh CC, Wang LY, et al. Risk factors for stomach cancer: A population-based case-control study in Shanghai. Cancer Causes Control, 1991,2:169-174.
59. Gonzaelez CA, Sanz JM, Marcos G, et al. Dietary factors and stomach cancer in spain: A multi-centre case-control study. Int J Cancer, 1991,49:513-519.
60. Demirer T, Icli F, Uzunalimoglu O, et al. Diet and stomach cancer incidence: A case-control study in Turkey. Cancer, 1990,65:2344-2348.
61. Corella D, Cortina P, Guillen M, et al. Dietary habits and geographic variation in stomach cancer mortality in Spain. Eur J Cancer Prev, 1996,5(4):249-257.
62．徐国平，宋圃菊．茶叶阻断胃癌高发区人体内源性N-亚硝基脯氨酸合成．北京医科大学学报，1991，23(2)：151-153．
63．任大林，靳建鸣，王笃圣等．天津市胃癌发病因素的探讨Ⅱ饮食与胃癌发病的关系．天津医药，1992，12：711－714．
64. Yu GP, Hsieh CC, Wang LY, et al. Green tea consumption and risk of stomach cancer: A population-based case-control study in Shanghai, China. Cancer Causes Control. 1995,6:572-578.
65. Correa P. A human model of gastric carcinogenesis. Cancer Res, 1988,48:3554-3560.
66. Inoue M, Tajima K, Kobayashi S, et al. Protective factor against progression from atrophic gastritis to gastric cancer-data from a chhot study in Japan. Iht J Cancer, 1996,66:309-314.
67. Watabe K, Nishi M, Miybe H, et al. Lifestyle and gastric cancer: a case-control study. Oncol Rep. 1998,5(5):1191-1194.
68．侯浚，乔翠云，孟凡书等．河北省磁县食管癌危险因素病例对照研究．中国肿瘤．1999，8(6)：252-255．
2．李连弟，鲁凤珠，张思维等．1990～1992年中国恶性肿瘤死亡流行分布情况分析．中华肿瘤杂志，1996，18(6)：403-407．
3．卜绍唐，熊宗幡．江苏省人口全死因研究．南京：东南大学出版社，1996．
4．潘凤娣．金坛市恶性肿瘤死亡动态特点研究．中国公共卫生，1999，15(2)：114-115．
5．王彬，陈瑾．徐天亮．肿瘤高发区江苏淮安1982～1996年主要恶性肿瘤死亡动态分析．肿瘤，1999，19(6)：361-362．
6．耿贯一主编．流行病学(第三卷)．第二版．北京：人民卫生出版社，1998：210-238．
7．薛开先．细胞色素P450多态及其在肿瘤易感性和突变中的进展．癌变，畸变，突变，1997，9(4)：256-259．
8. Gonzales FJ, Gelboin HV, Human cytochromes P450: evolution and cDNA-directed expression. Environmental Health Perspectives,1992,98:81-85.
9. Kato S, Peter GS, Neil EC, et al. Cytochrome P450 ⅡE1 genetic polymorphisms, racial variation, and lung cancer risk. Cancer Res,1992,52: 6712-6715.
10．林东昕，唐永明，彭琼等．细胞色素P4502E1和谷胱甘肽转硫酶P1基因与食管癌易患性．中华肿瘤杂志，1998，20(2)：94-97．
11. Yu MW, Alicja GY, Sinnabhatr C, et al. Cytochrome P4502E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology, 1995,109:1266-1273.
12. London SJ, Daly AK, Cooper J, et al. Lung cancer risk in relation to the CYP2E1 Rsa I genetic polymorphism among African-Americans and Caucasians in Los Angeles county. Pharmacogenetics, 1996,6:151-158.
13．沈洪兵．2型糖尿病的流行病学及高危险人群筛检方法研究．上海医科大学博士研究生毕业论文，1999．
14. Hirvonen A, Kirsti HP, Sisko A, et al. The human CYP2E1 gene and lung cancer: Dra I and Rsa I restriction fragment length polymorphisms in a Finnish study population. Carcinogenesis, 1993,14(1):85-88.
15. Tsutsumi M, Takada A, Wang JS. Genetic polymorphisms of cytochrome P4502E1 related to the development of alcoholic liver disease. Gastroenterology, 1994,107:1430-1435.
16. Hayashi S, Watanabe J, Kawajiri K. Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P4502E1 gene. J Biochem, 1991,110:559-565.
17．贺智敏，陈主初．CYP2E1基因及其多态性与化学致癌易感性．国外医学病理科学与临床分册，1998，18(4)：292-294．
18. Uematsu F, Ikawa S, Kikuchi H, et al. Restriction fragment length polymorphism of the human CYP2E1(cytochrome P450 ⅡE1) gene and susceptibility to lung cancer: possible relevance to low smoking exposure. Pharmacogenetics, 1994,4:58-63.
19. Maezawa Y, Masayoshi Y, Gotaro T Association between restriction fragment length polymorphism of the human cytochrome P450 Ⅱ E1 gene and susceptibility to alcoholic liver cirrhosis. The American J of Gastroenterology, 1994,89(4): 561-565.
20．王立东，刑莹，周琦．大鼠食管上皮细胞色素P4502E1和谷胱甘肽S-转移酶的初步研究．河南医科大学学报，1995，30(2)：132-134．
21．楚建军，徐耀初，叶本法等．消化道肿瘤高发区腌菜N-亚硝基化合物含量及致突变作用．中华预防医学杂志，1994，28(4)：202-205．
22. Correa E Human gastric carcinogenesis: a multistep and multifactorial process-first American Cancer Society Award Lecture on epidemiology and prevention. Cancer Res, 1992,52:6735-6740.
23. Awasthi YC, Sharma R, Singhalss. Human glutathione S-transferase. Int J Biochem, 1994,26:295-308.
24. Seidegard J, Pero RW, Miller DG, et al. A glutathione transferase in human leukocytes as a marker for the susceptibility to lung cancer. Carcinogenesis, 1986,7:751-753.
25. Valle NS, Motulsky AG, Eaton DL, et al. The glutathione S-transferase polymorphism as a marker for susceptibility to lung carcinoma. Cancer Res, 1993,53:2313-2318.
26．边建超，王金兵，吴燕等．GSTM1空白基因型与原发性肝细胞癌遗传易感性的研究．中华医学遗传学杂志，1996，13(6)：353-356．
27. Bell DA, Talor JA, Paulson DF, et al. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1(GSTM1) that increase susceptibility to bladder cancer. J Natl Cancer Inst, 1993,85(14): 1159-1164.
28. Brockmoeller J, Kerb R, Drakoulis N, et al. Glutathione S-transferase M1 and its variants A and B as host factors of bladder cancer susceptibility: a case-control study. Cancer Res, 1994,54:4103-4111.
29. Zhong S, Wyllie AH, Wolf CR. et al. Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis, 1993,14(9): 1821-1824.
30. Sato M, Sato I, Izumo T, et al. Genetic polymorphism of drug-metabolizing enzymes and susceptibility to oral cancer. Carcinogenesis, 1999,20(10): 1927-1931.
31. Board PG. Biochemical genetics of glutathione S-transferase in man. Am J Hum Genet, 1980,33:36-43.
32. Warholm M, Guthenberg C, Mannervik B. Molecular and catalytic properties of glutathione transferase μfrom human liver: an enzyme efficiently conjugating epoxides. Biochemistry,1983,22:3610-3617.
33. Wiencke JK, Pemble S, Ketterer B, et al. Gene deletion of glutathione transferase theta 1: Correlation with induced genetic damage and potential role in endogenous mutagenesis. Cancer Epid Biomarkers Prev, 1995,4:253-260.
34. Pemble S, Schroeder KR, Spencer SR, et al. Human glutathione S-transferase theta(GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J,1994,300:271-276.
35. Pearson WR, Vorachek WR, Xu SJ, et al. Identification of class-mu glutathione transferase genes GSTM1-GSTM5 on human chromosome lp13. Am J Hum Genet, 1993,53(1):220-233.
36. Lin HJ, Han CY, Bemstein DA, et al. Ethnic distribution of the glutathione transferase Mu 1-1 (GSTM1) null genotye in 1473 individuals and application to bladder cancer susceptibility. Carcinogenesis, 1994,15(5): 1077-1081.
37. Deakin M, James E, Charles H, et al. Glutathione S-transferase GSTT1 genotypes and susceptibility to cancer: studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers. Carcinogenesis,1996,17(4):881-884.
38．蔡琳，俞顺章，陈建顺．谷胱甘肽转硫酶M1、T1基因型与胃癌易感性的关系．中华预防医学杂志，1999，33(6)：331-333．
39．潘凯枫，吕有勇，谭文等．谷胱甘肽转硫酶M1和T1基因缺失与胃癌风险．中华预防医学杂志，1999，33(Suppl)：24-26．
40. Warholm M, Rane A, Alexandrie A, et al. Genotypic and phenotypic determination of polymorphic glutathione transferase T1 in a Swedish population. Pharmacogenetics, 1995,5:252-254.
41. Chenevix-Trench G, Young J, Coggan M, et al. Glutathione S-transferase M1 and T1 polymorphisms: susceptibility to colon cancer and age of onset. Carcinogenesis,1995,16:1655-1657.
42. Elexpuru-Camiruaga J, Buxton N, Kandula V, et al. Susceptibility to astrocytoma and meningioma: influence of allelism at glutathione S-transferase (GSTT1 and GSTM1) and cytochrome P-450(CYP2D6) loci. Cancer Res, 1995,55:4237-4239.
43. Nelson HH, Wiencke JK, Christiani DC, et al. Ethnic differences in the prevalence of the homozygous deleted genotype of glutathione S-transferase theta. Carcinogenesis, 1995,16:1243-1245.
44. Katon T, Naoki N, Yusuke K, et al. Glutathione S-transferase M1(GSTM1) and T1(GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis, 1996,17(9): 1855-1859.
45. Jourenkova-Mironova N, Voho A, Bouchardy C, et al. Glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes and the risk of smoking-related oral and pharyngeal cancers. Int J Cancer, 1999,81(1):44-48.
46. Setiawan VW, Zhang ZF, Yu GP, et al. GSTT1 and GSTM1 null genotypes and the risk of gastric cancer: a case-control study in a Chinese population. Cancer-Epidemiol-Biomarkers-Prev,2000,9(1):73-80.
47. Smith CAD, Smith G, Wolf CR, et al. Genetic polymorphisms in xenobiotic metabolism. Eur J Cancer, 1994,30A: 1935-1941.
48. Brockmoller J, Kerb R, Drakoulis N, et al. Genotype and phenotype of glutathione S-transferase class μ isoenzyme μ and ψ in lung cancer patients and controls. Cancer Res, 1993,53(5):1004-1011.
49. Walker AM. Proportion of disease attributable to the combined effect of two factors. Int J Epidemiol, 1981,10:81-85.
50．戴文灿，王声涌，陈英等．病因分值在病例对照研究中的应用—肺癌危险因素的交互效应．中华流行病学杂志，1997，18(6)：341-344．
51. Nebert DW. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet, 1997,60:265-271.
52. Genetic polymorphism of CYF2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias. Carcinogenesis, 1999,20(7): 1225-1229.
53. Inoue M, Tajima K, Yamamura Y, et al. Family history and subsite of gastric cancer: Data from a case-referent study in Japan. Int J Cancer, 1998,76:801-805.
54. Bartsch H, Montesano R. Relevance of nitrosamines to human cancer. Carcinogenesis(Lond.), 1984,5(1381-1393).
55. Lu SH, Ohshima H, Fu HM, et al. Urinary excretion of N-nitrosamino acids and nitrate by inhabitants of high-and low-risk areas for esophageal cancer in northern China: endogenous formation of nitrosoproline and its inhibition by vitamin C. Cancer Res, 1986,46:1485-1491.
56．陈君石，闻芝梅主译．食物、营养与癌症预防．上海：上海医科大学出版社，1999：152-185．
57．季川，李铭新．林县酸菜在食管癌病因中作用的研究：Ⅱ酸菜中亚硝胺及其前体物的检测．中国医学科学院学报，1991，13：230-232．
58. Yu GP, Hsieh CC, Wang LY, et al. Risk factors for stomach cancer: A population-based case-control study in Shanghai. Cancer Causes Control, 1991,2:169-174.
59. Gonzaelez CA, Sanz JM, Marcos G, et al. Dietary factors and stomach cancer in spain: A multi-centre case-control study. Int J Cancer, 1991,49:513-519.
60. Demirer T, Icli F, Uzunalimoglu O, et al. Diet and stomach cancer incidence: A case-control study in Turkey. Cancer, 1990,65:2344-2348.
61. Corella D, Cortina P, Guillen M, et al. Dietary habits and geographic variation in stomach cancer mortality in Spain. Eur J Cancer Prev, 1996,5(4):249-257.
62．徐国平，宋圃菊．茶叶阻断胃癌高发区人体内源性N-亚硝基脯氨酸合成．北京医科大学学报，1991，23(2)：151-153．
63．任大林，靳建鸣，王笃圣等．天津市胃癌发病因素的探讨Ⅱ饮食与胃癌发病的关系．天津医药，1992，12：711－714．
64. Yu GP, Hsieh CC, Wang LY, et al. Green tea consumption and risk of stomach cancer: A population-based case-control study in Shanghai, China. Cancer Causes Control. 1995,6:572-578.
65. Correa P. A human model of gastric carcinogenesis. Cancer Res, 1988,48:3554-3560.
66. Inoue M, Tajima K, Kobayashi S, et al. Protective factor against progression from atrophic gastritis to gastric cancer-data from a chhot study in Japan. Iht J Cancer, 1996,66:309-314.
67. Watabe K, Nishi M, Miybe H, et al. Lifestyle and gastric cancer: a case-control study. Oncol Rep. 1998,5(5):1191-1194.
68．侯浚，乔翠云，孟凡书等．河北省磁县食管癌危险因素病例对照研究．中国肿瘤．1999，8(6)：252-255．