Top

Published in:

01-02-2010 | Original paper

A comprehensive analysis of common genetic variation in MUC1, MUC5AC, MUC6 genes and risk of stomach cancer

Authors: Yanbin Jia, Christina Persson, Lifang Hou, Zongli Zheng, Meredith Yeager, Jolanta Lissowska, Stephen J. Chanock, Wong-Ho Chow, Weimin Ye

Published in: Cancer Causes & Control | Issue 2/2010

Abstract

Objective

MUC1, MUC5AC, and MUC6 are main constituents of the mucus barrier in the stomach, which protects the underlying epithelium from acid, proteases, mechanical trauma, and pathogenic microorganisms. Accumulating evidence implicates potential roles of MUC1, MUC5AC, and MUC6 genetic variation in the development of stomach cancer.

Methods

We evaluated the relationship between common genetic variations in these genes and stomach cancer risk, using an LD-based tagSNP approach in a population-based case–control study conducted in Warsaw, Poland, during 1994–1996. We genotyped 6, 8, and 14 tagSNPs in MUC1, MUC5AC, and MUC6 genes, respectively, among 273 cases newly diagnosed with stomach cancer and 377 controls.

Results

Each of the six tagSNPs tested across the MUC1 region showed statistically significant associations with an increased risk of stomach cancer. Carriers of the haplotype ACTAA rare alleles of rs4971052, rs4276913, rs4971088, rs4971092, and rs4072037 had a nearly doubled risk (OR = 1.93, 95% CI = 1.49–2.48) compared to the referent haplotype GTAAG. Out of the eight tagSNPs across MUC5AC region, only minor allele of rs868903 was significantly associated with an increased risk of stomach cancer (OR = 1.80, 95% CI = 1.22–2.63).

Conclusions

Overall, our data provide evidence that some common variations in MUC1 and MUC5AC genes contribute to an elevated risk of stomach cancer. Further studies are needed to confirm these novel findings.

Available only for authorised users

Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108CrossRefPubMed

Schistosomes, liver flukes and Helicobacter pylori (1994) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7–14 June 1994. IARC Monogr Eval Carcinog Risks Hum 61:1–241

Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M et al (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345(11):784–789CrossRefPubMed

Peek RM Jr, Blaser MJ (2002) Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer 2(1):28–37CrossRefPubMed

Kim YS, Gum J Jr, Brockhausen I (1996) Mucin glycoproteins in neoplasia. Glycoconj J 13(5):693–707CrossRefPubMed

De Bolos C, Garrido M, Real FX (1995) MUC6 apomucin shows a distinct normal tissue distribution that correlates with Lewis antigen expression in the human stomach. Gastroenterology 109(3):723–734CrossRefPubMed

Gendler SJ, Spicer AP (1995) Epithelial mucin genes. Annu Rev Physiol 57:607–634CrossRefPubMed

Audie JP, Janin A, Porchet N, Copin MC, Gosselin B, Aubert JP (1993) Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. J Histochem Cytochem 41(10):1479–1485PubMed

Babu SD, Jayanthi V, Devaraj N, Reis CA, Devaraj H (2006) Expression profile of mucins (MUC2, MUC5AC and MUC6) in Helicobacter pylori infected pre-neoplastic and neoplastic human gastric epithelium. Mol Cancer 5:10CrossRefPubMed

10.

Wang RQ, Fang DC (2006) Effects of Helicobacter pylori infection on mucin expression in gastric carcinoma and pericancerous tissues. J Gastroenterol Hepatol 21(2):425–431CrossRefPubMed

11.

Reis CA, David L, Correa P, Carneiro F, de Bolos C, Garcia E et al (1999) Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression. Cancer Res 59(5):1003–1007PubMed

12.

Reis CA, David L, Nielsen PA, Clausen H, Mirgorodskaya K, Roepstorff P et al (1997) Immunohistochemical study of MUC5AC expression in human gastric carcinomas using a novel monoclonal antibody. Int J Cancer 74(1):112–121CrossRefPubMed

13.

Carrato C, Balague C, de Bolos C, Gonzalez E, Gambus G, Planas J et al (1994) Differential apomucin expression in normal and neoplastic human gastrointestinal tissues. Gastroenterology 107(1):160–172PubMed

14.

Kocer B, Ulas M, Ustundag Y, Erdogan S, Karabeyoglu M, Yldrm O et al (2004) A confirmatory report for the close interaction of Helicobacter pylori with gastric epithelial MUC5AC expression. J Clin Gastroenterol 38(6):496–502CrossRefPubMed

15.

Van de Bovenkamp JH, Mahdavi J, Korteland-Van Male AM, Buller HA, Einerhand AW, Boren T et al (2003) The MUC5AC glycoprotein is the primary receptor for Helicobacter pylori in the human stomach. Helicobacter 8(5):521–532CrossRefPubMed

16.

Vinall LE, King M, Novelli M, Green CA, Daniels G, Hilkens J et al (2002) Altered expression and allelic association of the hypervariable membrane mucin MUC1 in Helicobacter pylori gastritis. Gastroenterology 123(1):41–49CrossRefPubMed

17.

Reis CA, David L, Carvalho F, Mandel U, de Bolos C, Mirgorodskaya E et al (2000) Immunohistochemical study of the expression of MUC6 mucin and co-expression of other secreted mucins (MUC5AC and MUC2) in human gastric carcinomas. J Histochem Cytochem 48(3):377–388PubMed

18.

Ho SB, Shekels LL, Toribara NW, Kim YS, Lyftogt C, Cherwitz DL et al (1995) Mucin gene expression in normal, preneoplastic, and neoplastic human gastric epithelium. Cancer Res 55(12):2681–2690PubMed

19.

Baldus SE, Hanisch FG (2000) Biochemistry and pathological importance of mucin-associated antigens in gastrointestinal neoplasia. Adv Cancer Res 79:201–248CrossRefPubMed

20.

Carvalho F, Seruca R, David L, Amorim A, Seixas M, Bennett E et al (1997) MUC1 gene polymorphism and gastric cancer–an epidemiological study. Glycoconj J 14(1):107–111CrossRefPubMed

21.

Silva F, Carvalho F, Peixoto A, Seixas M, Almeida R, Carneiro F et al (2001) MUC1 gene polymorphism in the gastric carcinogenesis pathway. Eur J Hum Genet 9(7):548–552CrossRefPubMed

22.

Nguyen TV, Janssen M Jr, Gritters P, te Morsche RH, Drenth JP, van Asten H et al (2006) Short mucin 6 alleles are associated with H. pylori infection. World J Gastroenterol 12(37):6021–6025PubMed

23.

Garcia E, Carvalho F, Amorim A, David L (1997) MUC6 gene polymorphism in healthy individuals and in gastric cancer patients from northern Portugal. Cancer Epidemiol Biomarkers Prev 6(12):1071–1074PubMed

24.

Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74(1):106–120CrossRefPubMed

25.

Westfall P, Young S (1993) Resampling-based multiple testing: examples and methods for p-value adjustment. Wiley, USA

26.

Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265CrossRefPubMed

27.

French B, Lumley T, Monks SA, Rice KM, Hindorff LA, Reiner AP et al (2006) Simple estimates of haplotype relative risks in case–control data. Genet Epidemiol 30(6):485–494CrossRefPubMed

28.

Ligtenberg MJ, Gennissen AM, Vos HL, Hilkens J (1991) A single nucleotide polymorphism in an exon dictates allele dependent differential splicing of episialin mRNA. Nucleic Acids Res 19(2):297–301CrossRefPubMed

29.

Imbert Y, Darling DS, Jumblatt MM, Foulks GN, Couzin EG, Steele PS et al (2006) MUC1 splice variants in human ocular surface tissues: possible differences between dry eye patients and normal controls. Exp Eye Res 83(3):493–501CrossRefPubMed

30.

Ng W, Loh AX, Teixeira AS, Pereira SP, Swallow DM (2008) Genetic regulation of MUC1 alternative splicing in human tissues. Br J Cancer 99(6):978–985CrossRefPubMed

31.

Pigny P, Guyonnet-Duperat V, Hill AS, Pratt WS, Galiegue-Zouitina S, d’Hooge MC et al (1996) Human mucin genes assigned to 11p15.5: identification and organization of a cluster of genes. Genomics 38(3):340–352CrossRefPubMed

32.

Baffa R, Negrini M, Mandes B, Rugge M, Ranzani GN, Hirohashi S et al (1996) Loss of heterozygosity for chromosome 11 in adenocarcinoma of the stomach. Cancer Res 56(2):268–272PubMed

33.

Moskaluk CA, Rumpel CA (1998) Allelic deletion in 11p15 is a common occurrence in esophageal and gastric adenocarcinoma. Cancer 83(2):232–239CrossRefPubMed

34.

Baldus SE, Monig SP, Arkenau V, Hanisch FG, Schneider PM, Thiele J et al (2002) Correlation of MUC5AC immunoreactivity with histopathological subtypes and prognosis of gastric carcinoma. Ann Surg Oncol 9(9):887–893CrossRefPubMed

35.

Lancaster CA, Peat N, Duhig T, Wilson D, Taylor-Papadimitriou J, Gendler SJ (1990) Structure and expression of the human polymorphic epithelial mucin gene: an expressed VNTR unit. Biochem Biophys Res Commun 173(3):1019–1029CrossRefPubMed

36.

Montpetit A, Nelis M, Laflamme P, Magi R, Ke X, Remm M et al (2006) An evaluation of the performance of tag SNPs derived from HapMap in a Caucasian population. PLoS Genet 2(3):e27CrossRefPubMed

37.

Lundmark PE, Liljedahl U, Boomsma DI, Mannila H, Martin NG, Palotie A et al (2008) Evaluation of HapMap data in six populations of European descent. Eur J Hum Genet 16(9):1142–1150CrossRefPubMed

38.

Lan Q, Chow WH, Lissowska J, Hein DW, Buetow K, Engel LS et al (2001) Glutathione S-transferase genotypes and stomach cancer in a population-based case–control study in Warsaw, Poland. Pharmacogenetics 11(8):655–661CrossRefPubMed

Title: A comprehensive analysis of common genetic variation in MUC1, MUC5AC, MUC6 genes and risk of stomach cancer
Authors: Yanbin Jia
Christina Persson
Lifang Hou
Zongli Zheng
Meredith Yeager
Jolanta Lissowska
Stephen J. Chanock
Wong-Ho Chow
Weimin Ye
Publication date: 01-02-2010
Publisher: Springer Netherlands
Published in: Cancer Causes & Control / Issue 2/2010
Print ISSN: 0957-5243
Electronic ISSN: 1573-7225
DOI: https://doi.org/10.1007/s10552-009-9463-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2010

Genetic variation in DNA repair genes and prostate cancer risk: results from a population-based study

Active, but not passive cigarette smoking was inversely associated with mammographic density

Determinants of inequalities in cervical cancer stage at diagnosis and survival in New Zealand

Depression and cancer risk: 24 years of follow-up of the Baltimore Epidemiologic Catchment Area sample

Serum calcium levels are elevated among women with untreated postmenopausal breast cancer

Intentional weight loss and risk of lymphohematopoietic cancers

Keynote webinar | Spotlight on antibody–drug conjugates in cancer