A case–control study on the effect of Apolipoprotein E genotypes on gastric cancer risk and progression

BMC Cancer

Emma De Feo³  Benedetto Simone³  Roberto Persiani²  Ferdinando Cananzi²  Alberto Biondi²  Dario Arzani³  Rosarita Amore³  Domenico D’Ugo²  Gualtiero Ricciardi³  Stefania Boccia¹ 

[1] IRCCS San Raffaele Pisana, Rome, Italy

[2] Department of Surgery, Università Cattolica del Sacro Cuore, Rome, Italy

[3] Institute of Hygiene, Università Cattolica del Sacro Cuore, Rome, Italy

关键词: Gene-environment interaction;    Polymorphism;    Genetic epidemiology;    Apolipoprotein E;    Gastric cancer;   

Others  :  1080116
DOI  :  10.1186/1471-2407-12-494

 received in 2012-03-08, accepted in 2012-10-11,  发布年份 2012

【 摘 要 】

Background

Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far.

Methods

One hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan–Meier analysis and Cox proportional hazard regression model.

Results

Subjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 – 0.84) compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium.

Conclusions

Our study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study’s sample size, further studies are required to confirm our findings.

【 授权许可】

   
2012 De Feo et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Mahley RW, Huang Y: Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing. J Clin Invest 2007, 17:94-98.
• [2]Vogel T, Guo NH, Guy R, et al.: Apolipoprotein E: a potent inhibitor of endothelial and tumor cell proliferation. J Cell Biochem 1994, 54:299-308.
• [3]Moore LE, Brennan P, Karami S: Apolipoprotein E/C1 locus variants modify renal cell carcinoma risk. Cancer Res 2009, 69:8001-8008.
• [4]Mahley RW, Nathan BP, Pitas RE: Apolipoprotein E: Structure, function, and possible roles in Alzheimer's disease. Ann N Y Acad Sci 1996, 777:139-145.
• [5]Bennet AM, Di Angelantonio E, Ye Z, et al.: Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007, 298:1300-1311.
• [6]Brouwers N, Sleegers K, Van Broeckhoven C: Molecular genetics of Alzheimer's disease: an update. Ann Med 2008, 40:562-583.
• [7]Jacobs D, Blackburn H, Higgins M, et al.: Report of the Conference on Low Blood Cholesterol: Mortality Associations. Circulation 1992, 86:1046-1060.
• [8]Delahaye F, Bruckert E, Thomas D, Emmerich J, Richard JL: Serum cholesterol and cancer. Is there a casual relationship? Arch Mal Coeur Vaiss 1992, 85:37-45.
• [9]Forones NM, Falcao JB, Mattos D, Barone B: Cholesterolemia in colorectal cancer. Hepatogastroenterology 1998, 45:1531-1534.
• [10]Asano K, Kubo M, Yonemoto K, et al.: Impact of serum total cholesterol on the incidence of gastric cancer in a population-based prospective study: the Hisayama study. Int J Cancer 2008, 122:909-914.
• [11]Kritchevsky SB, Kritchevsky D: Serum cholesterol and cancer risk: an epidemiologic perspective. Annu Rev Nutr 1992, 12:391-416.
• [12]Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G: Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008, 27:1133-1163.
• [13]Benn M, Tybjærg-Hansen A, Stender S, Frikke-Schmidt R, Nordestgaard BG: Low-density lipoprotein cholesterol and the risk of cancer: a mendelian randomization study. J Natl Cancer Inst 2011, 103:508-519.
• [14]Trompet S, Jukema JW, Katan MB, et al.: Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study. Am J Epidemiol 2009, 170:1415-1421.
• [15]Folsom AR, Peacock JM, Boerwinkle E: Sequence variation in protein convertase subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence. Cancer Epidemiol Biomarkers Prev 2007, 16:2455-2458.
• [16]Tornberg SA, Carstensen JM, Holm LE: Risk of stomach cancer in association with serum cholesterol and beta-lipoprotein. Acta Oncol 1988, 27:39-42.
• [17]Knekt P, Reunanen A, Aromaa A, Heliovaara M, Hakulinen T, Hakama M: Serum cholesterol and risk of cancer in a cohort of 39,000 men and women. J Clin Epidemiol 1988, 41:519-530.
• [18]Iso H, Ikeda A, Inoue M, Sato S, Tsugane S, for the JPHC Study Group: Serum cholesterol levels in relation to the incidence of cancer: The JPHC study cohorts. Int J Cancer 2009, 125:2679-2686.
• [19]Mrkonjic M, Chappell E, Pethe VV, et al.: Association of apolipoprotein E polymorphisms and dietary factors in colorectal cancer. Br J Cancer 2009, 100:1966-1974.
• [20]Slattery ML, Sweeney C, Murtaugh M, et al.: Associations between apoE genotype and colon and rectal cancer. Carcinogenesis 2005, 26:1422-1429.
• [21]Chang NW, Chen DR, Wu CT, et al.: Influences of apolipoprotein E polymorphism on the risk for breast cancer and HER2/neu status in Taiwan. Breast Cancer Res Treat 2005, 90:257-261.
• [22]Andreotti G, Chen J, Gao YT, et al.: Polymorphisms of genes in the lipid metabolism pathway and risk of biliary tract cancers and stones: a population-based case–control study in Shanghai, China. Cancer Epidemiol Biomarkers Prev 2008, 17:525-534.
• [23]Schatzkin A, Hoover RN, Taylor PR, et al.: Site-specific analysis of total serum cholesterol and incident cancers in the National Health and Nutrition Examination Survey I epidemiologic follow-up study. Cancer Res 1998, 48:452-458.
• [24]De Feo E, Rowell J, Cadoni G, Nicolotti N, Arzani D, Giorgio A, Amore R, Paludetti G, Ricciardi G, Boccia S: A case–control study on the effect of apoliprotein E genotype on head and neck cancer risk. Cancer Epidemiol Biomarkers Prev 2010, 19:2839-2846.
• [25]Jofre-Monseny LO, Minihane AM, Rimbach G: Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res 2008, 52:131-145.
• [26]Talmud PJ, Stephens JW, Hawe E, et al.: The significant increase in cardiovascular disease risk in ApoE4 carriers is evident only in men who smoke: Potential relationship between reduced antioxidant status and ApoE4. Ann Hum Genet 2005, 69:613-622.
• [27]Dietrich M, Hua Y, Block G, et al.: Associations between apolipoprotein E genotype and circulating F2- isoprostane levels in humans. Lipids 2005, 40:329-334.
• [28]Tsuda M, Sanada M, Nakagawa H, Kodama I, Sakashita T, Ohama K: Phenotype of apolipoprotein E influences the lipid metabolic response of postmenopausal women to hormone replacement therapy. Maturitas 2001, 38:297-304.
• [29]Xie K, Huang S: Regulation of cancer metastasis by tumor associated stress factors. Clin Exp Metastasis 2003, 20:31-43.
• [30]Suzuki H, Nishizawa T, Tsugawa H, Mogami S, Hibi T: Roles of oxidative stress in stomach disorders. J Clin Biochem Nutr 2012, 50:35-39.
• [31]Pasupathi P, Saravanan G, Chinnaswamy P, Bakthavathsalam G: Effect of chronic smoking on lipid peroxidation and antioxidant status in gastric carcinoma patients. Indian J Gastroenterol 2009, 28:65-67.
• [32]Kekec Y, Paydas S, Tuli A, Zorludemir S, Sakman G, Seydaoglu G: Antioxidant enzyme levels in cases with gastrointesinal cancer. Eur J Intern Med 2009, 20:403-406.
• [33]Oh SS, Chang SC, Cai L, Cordon-Cardo C, Ding BG, Greenland S, He N, Jiang Q, Kheifets L, Le A, Lee YC, Liu S, Lu ML, Mao JT, Morgenstern H, Mu LN, Pantuck A, Papp JC, Park SL, Rao JY, Reuter VE, Tashkin DP, Wang H, You NC, Yu SZ, Zhao JK, Belldegrun A, Zhang ZF: Single nucleotide polymorphisms of 8 inflammation-related genes and their associations with smoking-related cancers. Int J Cancer 2010, 127:2169-2182.
• [34]Boccia S, Gianfagna F, Persiani R, La Greca A, Arzani D, Rausei S, D'ugo D, Magistrelli P, Villari P, Van Duijn CM, Ricciardi G: Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population. Biomarkers 2007, 12:635-644.
• [35]Boccia S, Sayed-Tabatabaei FA, Persiani R, Gianfagna F, Rausei S, Arzani D, La Greca A, D’Ugo D, La Torre G, van Duijn CM, Ricciardi G: Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case–control study in an Italian population. BMC Cancer 2007, 7:206. BioMed Central Full Text
• [36]De Feo E, Persiani R, La Greca A, Amore R, Arzani D, Rausei S, D’Ugo D, Magistrelli P, van Duijn CM, Ricciardi G, Boccia S: A case–control study on the effect of p53 and p73 polymorphisms on gastric cancer risk and progression in an Italian population. Mutat Res 2009, 675:60-65.
• [37]Lauren P: The two histological main types of gastric carcinoma: diffuse and so called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965, 64:31-49.
• [38]Sobin LH, Wittekind C: TNM classification of malignant tumors, UICC. New York: Wiley-Liss; 2002.
• [39]Seripa D, Signori E, Gravina C, Matera MG, Rinaldi M, Fazio VM: Simple and effective determination of apolipoprotein E genotypes by positive/negative polymerase chain reaction products. Diagn Mol Pathol 2006, 15:180-185.