摘要
Qidong(Jiangsu, China) has been of interest to cancer epidemiologists and biologists because, until recently, it was an endemic area for liver cancer, having amongst the highest incidence rates in the world. The establishment of the Qidong Cancer Registry together with the Qidong Liver Cancer Institute in 1972 has charted the patterns of liver cancer incidence and mortality in a stable population throughout a period of enormous economic, social, and environmental changes as well as of improvements in health care delivery. Updated incidence trends in Qidong are described. Notably, the China age-standardized incidence rate for liver cancer has dropped by over 50% in the past several decades. Molecular epidemiologic and genomic deep sequencing studies have affirmed that infection with hepatitis B virus as well as dietary exposure to aflatoxins through contamination of dietary staples such as corn, and to microcystins–blue-green algal toxins found in ditch and pond water – were likely important etiologic factors that account for the high incidence of liver cancer in this region. Public health initiatives to facilitate universal vaccination of newborns against HBV and to improve drinking water sources in this rural area, as well as economic and social mandates serendipitously facilitating dietary diversity, have led to precipitous declines in exposures to these etiologic factors, concomitantly driving substantive declines in the liver cancer incidence seen now in Qidong. In this regard, Qidong serves as a template for the global impact that a package of intervention strategies may exert on cancer burden.
Qidong(Jiangsu, China) has been of interest to cancer epidemiologists and biologists because, until recently, it was an endemic area for liver cancer, having amongst the highest incidence rates in the world. The establishment of the Qidong Cancer Registry together with the Qidong Liver Cancer Institute in 1972 has charted the patterns of liver cancer incidence and mortality in a stable population throughout a period of enormous economic, social, and environmental changes as well as of improvements in health care delivery. Updated incidence trends in Qidong are described. Notably, the China age-standardized incidence rate for liver cancer has dropped by over 50% in the past several decades. Molecular epidemiologic and genomic deep sequencing studies have affirmed that infection with hepatitis B virus as well as dietary exposure to aflatoxins through contamination of dietary staples such as corn, and to microcystins–blue-green algal toxins found in ditch and pond water – were likely important etiologic factors that account for the high incidence of liver cancer in this region. Public health initiatives to facilitate universal vaccination of newborns against HBV and to improve drinking water sources in this rural area, as well as economic and social mandates serendipitously facilitating dietary diversity, have led to precipitous declines in exposures to these etiologic factors, concomitantly driving substantive declines in the liver cancer incidence seen now in Qidong. In this regard, Qidong serves as a template for the global impact that a package of intervention strategies may exert on cancer burden.
引文
1.Qidong Annals Editorial Committee.Qidong county annals.Beijing:China Publishing House;1993;1-1155.
2.Editorial Committee.Atlas of cancer mortality in the people’s republic of China.Shanghai:China Map Press;1979.
3.Chen JG,Li WG,Shen ZC,Yao HY,Zhang BC,Zhu YR.Population-based cancer survival in Qidong,China.In:Sankaranarayanan R,Black R,Parkin DM.Cancer Survival in Developing Countries.Lyon:IARC;1998;27-35.
4.Bray F,Colombet M,Mery L,Pi?eros M,Znaor A,Zanetti R,eds.Cancer incidence in five continents,Vol.XI(electronic version).Lyon:IARC;Available from:http://ci5.iarc.fr,accessed[2019/01/18].
5.Stewart BW,Wild CP.World cancer report 2014.Lyon:IARC;2014;1-630.
6.Chen JG,Zhu J,Zhang YH,Lu JH.Cancer survival in Qidong,China,1992-2000.In:Sankaranarayanan R,Swaminathan R.Cancer Survival in Africa,Asia,the Caribbean and Central America.Lyon:IARC;2011;43-53.
7.Zhou J,Sun HC,Wang Z,Cong WM,Wang JH,Zeng MS,et al.Guidelines for diagnosis and treatment of primary liver cancer in China(2017 Edition).Liver Cancer.2018;7:235-60.
8.Zhu YR,Chen JG,Huang XY.Hepatocellular carcinoma in Qidong County.In:Tang ZY,Wu MC,Hsia RS.Primary Liver Cancer.Berlin:Springer;1989;202-24.
9.Chen JG,Parkin DM,Chen QG,Lu JH,Shen QJ,Zhang BC,et al.Screening for liver cancer:results of a randomised controlled trial in Qidong,China.J Med Screen.2003;10:204-9.
10.Chen JG,Zhang YH,Zhu J,Lu JH,Wang JB,Sun Y,et al.Early diagnosis and early treatment for liver cancer in Qidong:survival of patients and effectiveness of screening.Chin J Oncol.2017;39:946-51.
11.Ming LH,Thorgeirsson SS,Gail MH,Lu PX,Harris CC,Wang NJ,et al.Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong,China.Hepatology.2002;36:1214-20.
12.Chen JG,Lu JH,Zhu YR,Zhu J,Zhang YH.A thirty-one year prospective follow-up program on the HBs Ag carrier state and primary liver cancer in Qidong,China.Chin J Epidemiol.2010;31:721-6.
13.Szyma?ska K,Chen JG,Cui Y,Gong YY,Turner PC,Villar S,et al.TP53 R249S mutations,exposure to aflatoxin,and occurrence of hepatocellular carcinoma in a cohort of chronic hepatitis B virus carriers from Qidong,China.Cancer Epidemiol Biomarkers Prev.2009;18:1638-43.
14.Kensler TW,Roebuck BD,Wogan GN,Groopman JD.Aflatoxin:a50-year odyssey of mechanistic and translational toxicology.Toxicol Sci.2011;120:S28-48.
15.Wang JS,Qian GS,Zarba A,He X,Zhu YR,Zhang BC,et al.Temporal patterns of aflatoxin-albumin adducts in hepatitis Bsurface antigen-positive and antigen-negative residents of Daxin,Qidong County,People's Republic of China.Cancer Epidemiol Biomarkers Prev.1996;5:253-61.
16.Nishiwaki-Matsushima R,Nishiwaki S,Ohta T,Yoshizawa S,Suganuma M,Harada K,et al.Structure-function relationships of microcystins,liver tumor promoters,in interaction with protein phosphatase.Jpn J Cancer Res.1991;82:993-6.
17.Ueno Y,Nagata S,Tsutsumi T,Hasegawa A,Watanabe MF,Park HD,et al.Detection of microcystins,a blue-green algal hepatotoxin,in drinking water sampled in Haimen and Fusui,endemic areas of primary liver cancer in China,by highly sensitive immunoassay.Carcinogenesis.1996;17:1317-21.
18.Su D.Drinking water and liver cell cancer:an epidemiologic approach to the etiology of this disease in China.Chin Med J(Engl).1979;92:748-56.
19.Ross RK,Yuan JM,Yu MC,Wogan GN,Qian GS,Tu JT,et al.Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma.Lancet.1992;339:943-6.
20.Qian GS,Ross RK,Yu MC,Yuan JM,Gao YT,Henderson BE,et al.A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai,People’s Republic of China.Cancer Epidemiol Biomarkers Prev.1994;3:3-10.
21.Wang LY,Hatch M,Chen CJ,Levin B,You SL,Lu SN,et al.Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan.Int J Cancer.1996;67:620-5.
22.Yu MW,Lien JP,Chiu YH,Santella RM,Liaw YF,Chen CJ.Effect of aflatoxin metabolism and DNA adduct formation on hepatocellular carcinoma among chronic hepatitis B carriers in Taiwan.J Hepatol.1997;27:320-30.
23.Wang SS,O’Neill JP,Qian GS,Zhu YR,Wang JB,Armenian H,et al.Elevated HPRT mutation frequencies in aflatoxin-exposed residents of Daxin,Qidong County,People’s Republic of China.Carcinogenesis.1999;20:2181-4.
24.Aguilar F,Harris CC,Sun T,Hollstein M,Cerutti P.Geographic variation of p53 mutational profile in nonmalignant human liver.Science.1994;264:1317-9.
25.Duflot A,Hollstein M,Mehrotra R,Trepo C,Montesano R,Cova L.Absence of p53 mutation at codon 249 in duck hepatocellular carcinomas from the high incidence area of Qidong(China).Carcinogenesis.1994;15:1353-7.
26.Rashid A,Wang JS,Qian GS,Lu BX,Hamilton SR,Groopman JD.Genetic alterations in hepatocellular carcinomas:association between loss of chromosome 4q and p53 gene mutations.Br JCancer.1999;80:59-66.
27.Jackson PE,Qian GS,Friesen MD,Zhu YR,Lu P,Wang JB,et al.Specific p53 mutations detected in plasma and tumors of hepatocellular carcinoma patients by electrospray ionization mass spectrometry.Cancer Res.2001;61:33-5.
28.Jackson PE,Kuang SY,Wang JB,Strickland PT,Mu?oz A,Kensler TW,et al.Prospective detection of codon 249 mutations in plasma of hepatocellular carcinoma patients.Carcinogenesis.2003;24:1657-63.
29.Huang XH,Sun LH,Lu DD,Sun Y,Ma LJ,Zhang XR,et al.Codon249 mutation in exon 7 of p53 gene in plasma DNA:maybe a new early diagnostic marker of hepatocellular carcinoma in Qidong risk area,China.World J Gastroenterol.2003;9:692-5.
30.Zhang WL,He H,Zang MY,Wu QF,Zhao H,Lu LL,et al.Genetic features of aflatoxin-associated hepatocellular carcinoma.Gastroenterology.2017;153:249-62.
31.Huang MN,Yu W,Teoh WW,Ardin M,Jusakul A,Ng AWT,et al.Genome-scale mutational signatures of aflatoxin in cells,mice,and human tumors.Genome Res.2017;27:1475-86.
32.Baptista M,Kramvis A,Kew MC.High prevalence of 1762T 1764Amutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers.Hepatology.1999;29:946-53.
33.Kuang SY,Jackson PE,Wang JB,Lu PX,Mu?oz A,Qian GS,et al.Specific mutations of hepatitis B virus in plasma predict liver cancer development.Proc Natl Acad Sci USA.2004;101:3575-80.
34.Chen JG,Kuang SY,Egner PA,Lu JH,Zhu YR,Wang JB,et al.Acceleration to death from liver cancer in people with hepatitis Bviral mutations detected in plasma by mass spectrometry.Cancer Epidemiol Biomarkers Prev.2007;16:1213-8.
35.Mu?oz A,Chen JG,Egner PA,Marshall ML,Johnson JL,Schneider MF,et al.Predictive power of hepatitis B 1762T/1764A mutations in plasma for hepatocellular carcinoma risk in Qidong,China.Carcinogenesis.2011;32:860-5.
36.Zhu Y,Jin Y,Guo X,Bai X,Chen TY,Wang JB,et al.Comparison study on the complete sequence of hepatitis B virus identifies new mutations in core gene associated with hepatocellular carcinoma.Cancer Epidemiol Biomarkers Prev.2010;19:2623-30.
37.Qu LS,Zhang HF,Liu JX,Liu TT,Shen XZ,Chen TY,et al.Potential susceptibility mutations in C gene for hepatitis B-related hepatocellular carcinoma identified by a two-stage study in Qidong,China.Int J Mol Sci.2016;17:1708.
38.Qu LS,Liu JX,Liu TT,Shen XZ,Chen TY,Ni ZP,Lu CH.Association of hepatitis B virus pre-S deletions with the development of hepatocellular carcinoma in Qidong,China.PLo SOne.2014;9:e98257.
39.Qu CF,Chen TY,Fan CS,Zhan QM,Wang YT,Lu JH,et al.Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis Bintervention study:a cluster randomized controlled trial.PLo SMed.2014;11:e1001774.
40.Sun Z,Zhy Y,Stjernsward J,Hilleman M,Collins R,Zhen Y,et al.Design and compliance of HBV vaccination trial on newborns to prevent hepatocellular carcinoma and 5-year results of its pilot study.Cancer Detect Prev.1991;15:313-8.
41.Turner PC,Sylla A,Gong YY,Diallo MS,Sutcliffe AE,Hall AJ,et al.Reduction in exposure to carcinogenic aflatoxins by postharvest intervention measures in west Africa:a community-based intervention study.Lancet.2005;365:1950-6.
42.Chen JG,Egner PA,Ng D,Jacobson LP,Mu?oz A,Zhu YR,et al.Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China.Cancer Prev Res.2013;6:1038-45.
43.Wu F,Mitchell NJ,Male D,Kensler TW.Reduced foodborne toxin exposure is a benefit of improving dietary diversity.Toxicol Sci.2014;141:329-34.
44.Pitt JI,Wild CP,Baan RA,Gelderblom WCA,Miller JD,Riley RT,et al.Improving public health through mycotoxin control.Lyon:IARC;2012;131-42.
45.Kensler TW,Groopman JD,Sutter TR,Curphey TJ,Roebuck BD.Development of cancer chemopreventive agents:oltipraz as a paradigm.Chem Res Toxicol.1999;12:113-26.
46.Wang JS,Shen XN,He X,Zhu YR,Zhang BC,Wang JB,et al.Protective alterations in phase 1 and 2 metabolism of aflatoxin B 1by oltipraz in residents of Qidong,People's Republic of China.JNatl Cancer Inst.1999;91:347-54.
47.Breinholt V,Hendricks J,Pereira C,Arbogast D,Bailey G.Dietary chlorophyllin is a potent inhibitor of aflatoxin B1hepatocarcinogenesis in rainbow trout.Cancer Res.1995;55:57-62.
48.Fahey JW,Stephenson KK,Dinkova-Kostova AT,Egner PA,Kensler TW,Talalay P.Chlorophyll,chlorophyllin and related tetrapyrroles are significant inducers of mammalian phase 2cytoprotective genes.Carcinogenesis.2005;26:1247-55.
49.Egner PA,Wang JB,Zhu YR,Zhang BC,Wu Y,Zhang QN,et al.Chlorophyllin intervention reduces aflatoxin-DNA adducts in individuals at high risk for liver cancer.Proc Natl Acad Sci USA.2001;98:14601-6.
50.Kensler TW,Chen JG,Egner PA,Fahey JW,Jacobson LP,Stephenson KK,et al.Effects of glucosinolate-rich broccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenanthrene tetraols in a randomized clinical trial in He Zuo township,Qidong,People's Republic of China.Cancer Epidemiol Biomarkers Prev.2005;14:2605-13.
51.Kensler TW,Ng D,Carmella SG,Chen ML,Jacobson LP,Mu?oz A,et al.Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong,China.Carcinogenesis.2012;33:101-7.
52.Egner PA,Chen JG,Wang JB,Wu Y,Sun Y,Lu JH,et al.Bioavailability of sulforaphane from two broccoli sprout beverages:Results of a short-term,cross-over clinical trial in Qidong,China.Cancer Prev Res.2011;4:384-95.
53.Egner PA,Chen JG,Zarth AT,Ng DK,Wang JB,Kensler KH,et al.Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage:results of a randomized clinical trial in China.Cancer Prev Res.2014;7:813-23.
54.Fahey JW,Talalay P,Kensler TW.Notes from the field:“green”chemoprevention as frugal medicine.Cancer Prev Res.2012;5:179-88.
55.Bray F,Ferlay J,Soerjomataram I,Siegel RL,Torre LA,Jemal A.Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CACancer J Clin.2018;68:394-424.
56.Altekruse SF,Henley SJ,Cucinelli JE,Mc Glynn KA.Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States.Am J Gastroenterol.2014;109:542-53.
57.Tapper EB,Parikh ND.Mortality due to cirrhosis and liver cancer in the United States,1999-2016:observational study.BMJ.2018;362:k2817.
58.Xu Y,Wang L,He J,Bi Y,Li M,Wang T,et al.Prevalence and control of diabetes in Chinese adults.JAMA.2013;310:948-59.
59.Ramachandran A,Snehalatha C,Wan Ma RC.Diabetes in SouthEast Asia:an update.Diabetes Res Clin Pract.2014;103:231-7.
60.Pang YJ,Kartsonaki C,Turnbull I,Guo Y,Clarke R,Chen YP,et al.Diabetes,plasma glucose,and incidence of fatty liver,cirrhosis,and liver cancer:a prospective study of 0.5 million people.Hepatology.2018;68:1308-18.
61.Smith JW,Kroker-Lobos MF,Lazo M,Rivera-Andrade A,Egner PA,Wedemeyer H,et al.Aflatoxin and viral hepatitis exposures in Guatemala:molecular biomarkers reveal a unique profile of risk factors in a region of high liver cancer incidence.PLo S One.2017;12:e0189255.
62.Yu SZ.Primary prevention of hepatocellular carcinoma.JGastroenterol Hepatol.1995;10:674-82.
63.Chen JG.Cancer in Qidong,China 1972-2011.Beijing,China:Military Medical Science Press;2013;1-346.