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Clinical Chemistry 52: 1625-1627, 2006; 10.1373/clinchem.2006.071696
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(Clinical Chemistry. 2006;52:1625-1627.)
© 2006 American Association for Clinical Chemistry, Inc.

Letters to the Editor

A Mannose-Binding Lectin-Defective Haplotype Is a Risk Factor for Gastric Cancer

Olga Scudiero1, Gerardo Nardone2, Daniela Omodei1, Fabiana Tatangelo3, Dino Franco Vitale4, Francesco Salvatore1,a and Giuseppe Castaldo1,5

1 Dipartimento di Biochimica, e Biotecnologie Mediche, Università degli Studi di Napoli, "Federico II", and, CEINGE-Biotecnologie, Avanzate e SEMM, Naples, Italy
2 Dipartimento di Medicina, Interna e Sperimentale, Unità di Gastroenterologia, Università degli Studi di Napoli, "Federico II", Naples, Italy
3 Istituto dei Tumori, "Fondazione Pascale", Naples, Italy
4 Fondazione Salvatore Maugeri, IRCCS, Istituto Scientifico di Telese Terme, Benevento, Italy
5 Facoltà di Scienze, Università del Molise, Campobasso, Italy

aAddress correspondence to this author at: Dipartimento di Biochimica e Biotecnologie Mediche, via S. Pansini 5, 80131 Naples, Italy. Fax 39 081 746 36 50; e-mail salvator{at}unina.it.


To the Editor:

El-Omar et al. (1) reported that interleukin (IL)-1 gene cluster variants that enhance the production of IL-1ß (a powerful inhibitor of gastric acid secretion) increase the risk of gastric cancer in Helicobacter pylori (HP)-infected patients. IL-1ß production is down-regulated by mannose-binding lectin (MBL) (2), an acute-phase glycoprotein that has a high affinity for gram-negative lipopolysaccharide and exerts immunological activity (3)(4). Variants in the promoter, the 5'UTR, and exon 1 of the MBL2 gene reduce the synthesis and activity of MBL (5).

To assess the relationships between MBL2 gene variants and HP-related gastric cancer, we analyzed the whole coding region and the 5'UTR of the MBL2 gene in DNA extracted (QIAamp, Qiagen) from neoplastic cells embedded in paraffin sections (used for histological diagnosis) from 145 unrelated patients (90 males) affected by noncardia gastric cancer. Eighty-seven (60.0%) had intestinal-type; 47 (32.4%), diffuse-type; and 11 (7.6%), mixed-type adenocarcinoma. All patients had HP-positive serology. For 75 patients, we also analyzed DNA extracted from blood or from nonneoplastic surrounding tissue. All participants gave informed consent.

We examined DNA extracted from blood of 553 (240 males) unselected, unrelated, healthy adults from Southern Italy. For each DNA sample, we sequenced the promoter (–550 to –221), 5'UTR (–464 to +104), and exon 1 (–97 to +206) of the MBL2 gene in both directions. Primers, PCR mix, and conditions are available on request. MBL2 mutations in exon 1 at codons 54, 52, and 57 are called B, D, and C, respectively (5). The wild-type allele is "allele A". The 3 polymorphisms in the promoter region are called H/L (–550), X/Y (–221), and P/Q (+4 in the 5'UTR).

Analysis results for DNA from blood or from nonneoplastic tissue of 75 patients with gastric cancer invariably were the same as those for neoplastic tissue, excluding the possibility that MBL2 haplotypes were altered by somatic mutations.

The distribution of MBL2 haplotypes was in Hardy-Weinberg equilibrium in healthy individuals ({chi}2 not significant). The haplotype distribution differed significantly between healthy individuals and gastric cancer patients (global {chi}2: 23.4, P <0.001). The multiple comparison of each haplotype frequency tested against the others pooled together ({chi}2 or Fisher exact test as appropriate, with Bonferroni correction for multiple comparison) showed that only the HYPD haplotype was significantly different (Table 1 , part A). It was present in 4.4% of alleles from controls and in 10.4% of alleles from gastric cancer patients ({chi}2, 13.97; Bonferroni adjusted P = 0.00131). The distributions of the 6 other haplotypes were comparable in the 2 groups.


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  		Table 1. Number (and frequency) of mannose-binding lectin haplotypes (part A) and genotypes (part B) in patients affected by gastric cancer and in a population of healthy individuals.1

The R52C MBL2 mutation (allele D) alters the collagen-like domain of the MBL protein thereby limiting the formation of high-molecular-weight complexes and reducing the immunological activity of the protein (4). Participants bearing the D allele in heterozygosis (9 gastric cancer patients in the present study; Table 1Up , part B) have a 10-fold lower serum MBL concentration, and the immunological activity of the residual protein is very low because of impaired polymerization. Homozygotes for the D allele (3 gastric cancer patients in the present study; Table 1Up , part B) have no residual activity of the protein (5).

We suggest that the low MBL activity in patients bearing the HYPD haplotype may allow enhanced bacterial colonization of the gastric mucosa and reduce down-regulation of IL-1ß production, thereby increasing the risk of gastric cancer (odds ratio: 2.5; Table 1Up , part A). Indeed, IL-1ß production is up-regulated by HP. IL-1ß induces chronic hypochlorhydria, which promotes the spread of HP-induced inflammation and leads to gastric atrophy, a precursor of gastric cancer (1). Hypochlorhydria also promotes the colonization of other bacteria that foster mucosal damage and the production of carcinogenic compounds (1), adding to the scarce antibacterial activity of MBL caused by the HYPD haplotype. IL-1 gene polymorphisms that enhance IL-1ß production are associated with an increased risk of gastric cancer in HP-infected patients (1). Furthermore, the addition of sera containing unaffected MBL concentrations to monocytes stimulated by N. meningitidis down-regulates the production of IL-1ß, whereas the addition of sera from MBL-deficient individuals enhances the production of the cytokine (4). Otherwise, MBL2 HYPD haplotype may be in linkage disequilibrium with variants of other genes responsible for the increased risk of gastric cancer.

To conclude, the MBL2-defective HYPD haplotype may be a novel genetic marker of risk for gastric cancer in HP-infected patients.


Acknowledgments

This study was supported by Ministero dell’Istruzione, dell’Università e della Ricerca, Italy (PRIN 2004) and by Regione Campania (L. 229/99). We are indebted to Jean Gilder for editing the text.


References

  1. El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 2003;124:1193-1201.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  2. Jack DL, Read RC, Tenner AJ, Frosch M, Turner MW, Klein NJ. Mannose-binding lectin regulates the inflammatory response of human professional phagocytes to Neisseria meningitidis serogroup B. J Infect Dis 2001;184:1152-1162.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  3. Thielens NM, Cseh S, Thiel S, Vorup-Jensen T, Rossi V, Jensenius JC, et al. Interaction properties of human mannan-binding lectin (MBL)-associated serine proteases-1 and-2, MBL-associated protein 19, and MBL. J Immunol 2001;166:5068-5077.[Abstract/Free Full Text]
  4. Jack DL, Klein NJ, Turner MW. Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis. Immunol Rev 2001;180:86-99.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  5. Wallis R, Cheng JY. Molecular defects in variant forms of mannose-binding protein associated with immunodeficiency. J Immunol 1999;163:4953-4959.[Abstract/Free Full Text]



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