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[Cancer Research 61, 2684-2689, March 15, 2001]
© 2001 American Association for Cancer Research

Molecular Biology and Genetics

Gastric Cancer and Human Leukocyte Antigen

Distinct DQ and DR Alleles Are Associated with Development of Gastric Cancer and Infection by Helicobacter pylori1

Patrik K. E. Magnusson2, Helena Enroth2, Inger Eriksson, Maria Held, Olof Nyrén, Lars Engstrand, Lars-Erik Hansson and Ulf B. Gyllensten3

Department of Genetics and Pathology, Section of Medical Genetics, Rudbeck Laboratory, SE-751 85 Uppsala [P. K. E. M., I. E., U. B. G.]; Department of Medical Epidemiology, Karolinska Institutet, SE-171 77, Stockholm [H. E., M. H., O. N., L. E., L-E. H.]; and Smittskyddsinstitutet, SE-105 21 Stockholm [L. E.], Sweden


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
DNA and sera from 130 cases of gastric cancer and 263 population-based controls were analyzed to study the association of HLA class II DR-DQ alleles with Helicobacter pylori (Hp) infection and the risk for gastric cancer. Presence of the DQA1*0102 allele was inversely and significantly associated with Hp seropositivity (P = 2 x 10-5), which is an independent replication of previous findings. However, this inverse relationship with Hp did not correspond with a reduced risk of gastric cancer. At the DRB1 locus, the *1601 allele was significantly associated with an increased gastric cancer risk with an odds ratio (95% confidence interval) of 8.7 (range, 2.7–28.0). The effect of *1601 was more pronounced among Hp-negative subjects, and the association was stronger with the diffuse, rather than with the intestinal, histological type of gastric cancer. Because none of the HLA alleles were associated with both Hp infection and gastric cancer, the HLA DR-DQ alleles are linked with gastric cancer risk through other mechanisms than an increased susceptibility to Hp infection.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Infection with Hp4 is known to be strongly associated with development of gastric cancer (1) . Hp infection causes the onset of gastritis and thereby initiates a process that in certain individuals may develop into gastric cancer. Infection with Hp is common worldwide and about half of the human population is believed to be infected. Because only a small fraction of infected individuals develop gastric cancer, additional factors must be involved in the progression toward cancer. In some geographic regions, gastric cancer is aggregated in families (2 , 3) . In a subset of these families, germ-line mutations in the E-cadherin gene have been identified to predispose to diffuse type of gastric cancer with high penetrance (4) . Only a small fraction of all gastric cancer cases can, however, be attributed to these mutations. Other inherited factors may be of importance to cancer development. Putative genetic factors may either act independently of Hp or in synergy with the bacteria. Genetic predisposition to Hp infection is suggested by an estimated heritability of 0.67 as reported in a recent study on Swedish twins (5) . In animal models, genetic differences in the host response against infection by Helicobacter species result in varying intensity of inflammation and degree of gastric epithelial erosion (6) . Immunogenetic factors might influence the severity of inflammation and thereby also the different clinical outcomes. HLA class I and class II molecules, encoding cell surface {alpha}-ß heterodimers that bind and present peptides derived from foreign antigen to T cells, are among the host factors that may contribute to gastric cancer development. Alleles at HLA class I and class II loci have been found previously to be associated with pathogenic infections (7 , 8) as well as cervical (9) and nasopharyngeal (10) cancer. Several studies of the association between HLA type and gastric cancer have also been conducted (11, 12, 13) .


   SUBJECTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects.
The gastric cancer group consisted of 130 histologically verified gastric adenocarcinoma patients of Swedish origin. The case patients in the present study were consecutive, newly diagnosed gastric cancer patients from the catchment area of eight hospitals in central and northern Sweden. They constituted of a subset of a larger population-based case-control study in which all gastric cancer cases, diagnosed during 1989–1995 in five counties, were identified (14) . A comprehensive organization for case ascertainment, with contact persons at all hospitals, continuous surveillance at all pathology departments, and monthly double-checks with the regional and national cancer registries, continuing for several years after the study period, ensured a completeness that exceeded that of the Swedish cancer registry (14) . Of all eligible patients, 62% agreed to participate in the study. Reasons for nonparticipation were early death or very advanced disease in 30%, other mental or physical illnesses in 4%, patient refusal in 3%, and 0.3% could not be located.

The control group consisted of 263 individuals of Swedish origin. They were also a subset of the same population based study in which individuals were randomly selected from age and gender strata in the source population to mimic the expected age and gender distribution among gastric cancer patients. Among all controls that were selected for the larger population-based study, 76% agreed to participate. Reasons for nonparticipation were refusal in 16%, mental or physical illness in 6%, and 2% could not be located.

In the subsets of cases and controls (of the larger population-based study) that form the basis of the present study, the median year of birth for case-patients was 1919 and 1925 for the controls. The birth-year distribution was somewhat more widespread among the cases than among the controls. For the cases, the earliest birth-year was 1899, the 25% quartile 1910, the 75% quartile 1931, and the latest birth-year was 1963. For the controls, the earliest year of birth was 1912, the 25% quartile was 1921, the 75% quartile 1931, and the maximum was 1963. The male:female ratio was 1.45 (77 of 53) for the cases and 2.46 (187 of 76) for the controls.

Serology.
The presence of Hp infection was studied using the ELISA kit HM*CAP (Enteric Products, Westbury, MA), according to the protocol supplied by the manufacturer. The subjects were diagnosed as positive or negative for Hp if scoring above or below the cut-off value given by the manufacturer. Total IgG responses against Hp surface proteins were measured by Western blots of patient sera. The Hp strain CCUG 17874 was cultured for 2 days on selective agar plates according to standard procedures. The surface extract from these bacteria was produced by glycine extraction. The protein preparations were run on 12% SDS-acrylamide gels with a 5% stacking gel and transferred to NC-membranes. A mid-range molecular marker (Promega) was used on each gel, transferred to the membrane, and detected by Amidoblack. Western blots were performed with patient sera at a dilution of 1:75 on a shaker overnight at 4°C. Peroxidase-conjugated rabbit antihuman IgG (Dakopatts, Copenhagen, Denmark) was used as a secondary antibody at a dilution of 1:400. Incubation was performed for at least 2 h at 4°C. The blots were developed in 3-amino-9-ethylcarbazole for 10 min, washed in distilled water, and then air-dried before analysis and storage. The immunoblotting strips were visually scored as positive or negative for the protein CagA, based on the presence or absence of antibodies in the subjects sera against this particular protein band at Mr ~118,000–120,000.

DNA Extraction.
The DNA from gastric cancer patients was obtained from the serum fraction of blood samples. The cells in 1.5 ml of serum were pelleted in a microcentrifuge for 30 min. The pellet was dissolved in 200 ml of buffer [50 mM KCl, 10 mM Tris-HCl (pH 8.3), 2.5 mM MgCl2, 0.45% NP40, and 0.45% Tween 20], 4 µl of proteinase K (10 mg/ml) were added, and the mixture was incubated at 56°C for 1 h. The DNA was isolated by repeated organic extractions with phenol-chloroform and precipitated from the water-soluble phase by making the solution 0.3 M NaAc (pH 5.3) and by adding 2 volumes of 99.9% ethanol. The DNA pellet was washed in 70% ethanol, dried, and dissolved in 10 mM Tris-HCl (pH 7.5), 0.1 mM EDTA. The DNA from the controls was obtained from whole blood cells extracted by the standard phenol-chloroform procedure (15) . Briefly, DNA was extracted by mixing 0.5 ml of whole blood with 0.5 ml lysis solution [0.32 M sucrose, 10 mM Tris-HCl (pH 7.5), 5 mM MgCl2, and 1% Triton X-100]. The cells were washed in the lysis solution and pelleted twice by centrifugation. The nucleated cells were resuspended in 0.5 ml of digestion buffer [50 mM NaCl, 30 mM Tris-HCl (pH 7.5), 10 mM EDTA, and 100 mg/ml Proteinase K] and incubated at 55°C for 1–2 h. After extraction with phenol and chloroform, the DNA was precipitated and immediately dissolved in TE buffer [10 mM Tris-HCl (pH 7.5), 1 mM EDTA].

Genetic Typing of DQA1 and DRB1.
For typing of the DQA1 locus, a 242-bp fragment from the second exon was amplified using the primer pair GH26 and GH27 (16) . A total of 35 cycles of PCR (each consisting of 45 s at 94°C, 45 s at 55°C, and 45 s at 72°C) were performed, the PCR products were immobilized on nylon membranes and then hybridized to a set of eight oligonucleotides (17) . This typing system is not able to subdivide the DQA1-04 into the DQA1*0401, *0501, and *0601 alleles.

For PCR amplification of the DRB1-5 loci the primer pair GH46 and GH50 was used. A total of 40 cycles of 1 min at 94°C, 1 min at 55°C, and 1 min at 72°C were run. The 272-bp fragment product was, after membrane immobilization, hybridized to each of 19 probes (18) . A PCR specifically amplifying the DRB1 was performed by using the primers GH46 and CRX37 for 40 cycles, using the same thermocycle parameters as for GH46 and GH50. The GH46 and CRX37 primer pair does not amplify the DRB1 alleles *15-16, *07, and *09. The 297-bp fragment was hybridized to a second typing panel containing seven additional probes. For both DQA1 and DRB1 typing, the PCR products were denatured and applied onto Biodyne B membrane (Pall Corp.). The hybridization and washing procedures were performed according to published protocols (18) . Hybridization was detected using a chemiluminescent system (ECL) and exposure to Eastman Kodak Xomat-S X-ray film.

Statistical Analyses.
Relative risks were estimated by calculating age and sex adjusted ORs with 95% CIs and Ps using logistic regression (SAS procedure LOGISTIC), where sex and year of birth (quintiles) were included in the model. The probability of interactions was studied by using the GENMOD procedure in the SAS program. The sex-specific associations were adjusted for year of birth, and the birth-year group-specific associations were adjusted for sex. In the analyses of associations between HLA alleles and Hp infection or cancer, we considered carriers of a particular allele as exposed independently if they were homo- or heterozygotes. Because of the large number of alleles tested, the appropriate significance level was considered by Bonferroni correction for 44 alleles (39 minus one DRB1, plus 7 minus one DQA1), requiring a P <= 0.0011 to consider the result for a specific allele significant at the 95% level. Allele frequencies in cases and controls were calculated by direct counting of the alleles.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Infection with Hp and Risk of Gastric Cancer.
We investigated 130 patients with gastric cancer and 263 controls for Hp infection status. On the basis of the ELISA assay, 78% (101 of 130) of the patients and 54% (139 of 255) of the controls were positive for Hp, resulting in a OR (95% CI) of 3.2 (1.8–5.4). When detection of the CagA antigen by Western blotting was used as evidence of infection, 84% of the cases and 56% of the controls were positive, giving an OR (95% CI) of 5.1 (2.8–9.2) (Table 1)Citation . Among the ELISA-positive individuals, 94% of the cancer patients and 92.8% of the controls were also CagA positive. Interestingly, among the cancer cases that were negative for Hp, as determined by ELISA, 48.3% were CagA positive, whereas only 10.3% of the ELISA negative controls were positive for CagA.


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  		Table 1 Association between Hp, antibodies to the CagA protein, and gastric cancer

 
Because the population prevalence of Hp infection has decreased during the 20th century, we investigated the effect of Hp infection in different birth-year cohorts by comparing the fraction of seropositive subjects among cases and controls in five birth-year groups (quintiles). As can be seen in Fig. 1Citation , the difference in prevalence between cases and controls increase with increasing year of birth. This is mainly because of the decreasing Hp prevalence with birth-year in the controls. The time effect is striking when the association between seropositivity and cancer is analyzed for each age group separately (Table 1)Citation . When ELISA seropositivity is used as a criterion for infection, there is a clear trend of increasing OR with birth-year. Among individuals born before 1918 the OR is only 1.2, whereas it is as high as 17.5 among individuals born after 1933. When CagA is used for determining Hp infection, the effect of birth-year is still evident for the association, but less pronounced.



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  		Fig. 1. Birth-year group-specific prevalences of Hp infection by ELISA (not dotted) and by CagA (dotted) in the cases of gastric cancer ({square}) and controls ( ).

 
Age-corrected estimates of the effect of Hp infection were calculated for males and females separately. By using ELISA, a somewhat stronger association was observed in females (age adjusted OR, 6.3) than in males (age adjusted OR, 2.5); this difference was not observed when using CagA as an indication of Hp exposure (Table 1)Citation .

To study whether infection with Hp is associated with differences in excess risk for the two major histological types of gastric cancer, the diffuse and intestinal type, we performed the analyses with these two types as separate outcomes. The frequency of ELISA positivity is 84.3% among cases with the intestinal form, whereas it is only 66.7% among cases with the diffuse form. These results are consistent with those of some previous reports (19 , 20) , arguing for a stronger association of Hp with the intestinal, as compared with the diffuse, type of gastric cancer.

Influence of HLA Class II Alleles on Gastric Cancer Risk.
The association of HLA with gastric cancer was investigated in two steps:

(a) The association between the HLA class II loci DQA1 and DRB1 and Hp infection was analyzed by comparing the carrier frequency (frequency of individuals positive for a particular allele) of seronegative and seropositive subjects as measured by ELISA. Because infection with Hp is a risk factor in itself for gastric cancer development, we analyzed whether the effect was modified by cancer status. At the DQA1 locus, the *0102 allele occurs at a higher frequency among the uninfected, as compared with the infected subjects, resulting in a significant association (P = 2 x 10-5), which strongly suggest a protective effect of this allele against Hp infection. No interaction was found with cancer status (P = 0.32), and the magnitude of the effect is similar in both cancer cases and controls when analyzed separately (Tables 2Citation and Table 4Citation ). We also found the DRB1*1501 allele to be in higher frequency among uninfected as compared with infected individuals (Tables 3Citation and Table 4Citation ). This may reflect the strong linkage disequillibrium between the DRB1 and DQA1 loci (21) . The DQA1*0102 allele is found in haplotype combinations with a number of different DRB1 alleles, among which the *1501 allele is one. The other allele listed in Table 4Citation , the DQA1*0101, shows an association of weaker nature that is not significant after correction for multiple tests.


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  		Table 2 Allele frequencies at the DQA1 locus in gastric cancer patients and controls, stratified by Hp infection status

 

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  		Table 4 Associations between alleles of HLA and Hp infection estimated for gastric cancer cases and controls separately

 

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  		Table 3 Allele frequencies at the DRB1 locus in gastric cancer patients and controls, stratified by Hp infection status

 
(b) As a second step, we studied the association between HLA and development of gastric cancer, with measurements adjusted as well as stratified for Hp infection status. One DRB1 allele, the *1601, showed a highly significant difference in frequency between the cancer patients and the controls. The frequency of individuals carrying the DRB1*1601 allele is 13.4% among the cases, whereas it is only 2.0% among the controls (OR, 8.7; P = 3 x 10-4, Tables 3Citation and Table 5Citation ). The association of the DRB1*1601 allele is significant also after Bonferroni correction, indicative of a strong risk factor for development of gastric cancer. As can be seen in Table 5Citation , the effect of the DRB1*1601 is manifested more strongly in Hp-negative subjects, with an OR of 15.6, whereas the OR is three times lower in Hp-positive individuals (Table 5)Citation . However, the interaction effect of DRB1*1601 and infection is not significant (P = 0.07). Because gastric cancer of the intestinal and diffuse type appear to differ with respect to the degree of association with Hp infection, we also examined whether the association of DRB1*1601 differed between these two histological types of cancer. Using the two types of cancer as separate outcomes, the association with the diffuse type (OR, 27.5) is substantially stronger than for the intestinal type (OR, 3.8; Table 5Citation ). The DQA1*0201, DRB1*0701, and DRB1*1501 alleles also show association with gastric cancer. However, these alleles are less common among individuals with cancer than in the control group, and the associations are not significant after correction for multiple tests (Table 5)Citation .


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  		Table 5 Associations between alleles of HLA and gastric cancer

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our results provide further support for Hp infection as a major risk factor for gastric cancer. Still, more than half of the individuals in the control group were also infected, implying that factors other than Hp must also influence the risk of tumor development. Epidemiological evidence as well as direct mutation analyses have implicated genetic factors in the disease (2 , 3) , and because tumor development is preceded by chronic inflammation, immunological reactions, either toward the infectious agent itself or against tumor antigens, may be of importance for disease development. Polymorphisms in the interleukin 1 gene cluster have been proposed recently to modulate the risk of gastric cancer (22) , emphasizing that inherited variation in components of the immune system may be critical for gastric cancer development.

Analyses of the carrier frequencies of DRB1 and DQA1 alleles showed that different alleles are associated with Hp infection and cancer development, respectively. DQA1*0102 has been shown previously to be a protective factor in several (13 , 23 , 24) but not all (25) previous studies of HLA influence on Hp infection. Our result is an independent replication of previous positive studies and supports the notion that the DQA1*0102 allele is indeed associated with decreased risk of infection. However, we are unable to show that this allele will also protect (through an anti-Hp effect) against gastric cancer. Thus, the *0102 allele seems to be important mainly for the immune response to Hp infection.

The higher frequency of carriers of the DRB1*1601 allele in gastric cancer patients as compared with controls indicates that this allele is a strong risk factor for tumor development. The small P for this association (P = 3 x 10-4) makes it significant at the 95% level, even after taking the number of tests performed into account. The magnitude (in terms of OR) of the DRB1*1601 effect is 2–3-fold higher than the average effect of Hp. To investigate whether the association with DRB1*1601 is influenced by Hp infection, we studied the interaction with infection status. When including only Hp-positive subjects, the resulting OR was <5, whereas when only the negative subjects were considered, the OR was as high as 15.6. The P of this difference in effect is 0.07 and thereby not significant at the 95% level. Nevertheless, it is clear that the DRB1*1601 allele is associated mainly with cancer development, rather than infection.

A recently published twin-study suggested separate genetic factors for peptic ulcer disease and Hp infection (5) . The notion that we find distinct genetic factors (alleles) associated with gastric cancer and Hp infection, respectively, is in agreement with the existence of discrete genetic factors for Hp infection and its associated clinical manifestations, like peptic ulcer, as reported in the twin-study.

The majority of the subjects testing positive for Hp by ELISA were also positive for the CagA antigen by immunoblotting, both among cases (94%) and among controls (93%), showing that infection with strains not expressing the CagA antigen is uncommon in the Swedish population. In contrast, a large difference was found in the frequency of CagA-positive individuals among both ELISA-negative cases and controls. Almost half of the negative cases were positive by CagA immunoblotting, but only 10% of the negative controls were positive. The high frequency of CagA positivity among individuals that are Hp negative by ELISA suggests that the CagA immunoblotting method has a stronger potential to reveal past infections. Age has been shown to influence the association between Hp and gastric cancer (26 , 27) . In our study, the prevalence of infection decreases strongly with year of birth in the controls, whereas the prevalence appears to be more constant among the cases (Fig. 1)Citation . The observed difference in age trends between cancer patients and controls is of interest in relation to the proposition that the effect of Hp is systematically underestimated in cross-sectional case/control studies because of elimination of Hp infection in cases upon extended mucosal atrophy (28) . Such disappearance of infection could explain the observation that the Hp prevalence in cases does not increase with decreasing year of birth, as for the controls.

Previous studies have reported a stronger association with Hp for the intestinal as compared with the diffuse type of gastric cancer (19 , 20) . Our data support that the two histological types show different degrees of association with Hp infection; the frequency of ELISA positivity is 84.3 and 66.7% for the intestinal and diffuse cases, respectively. Such a difference might reflect that diffuse cancers are less dependent on infection for their development, or, potentially, that spontaneous loss of infection upon cancer development is more common in this type of cancer.

We also examined whether the association of DRB1*1601 depends on the type of cancer. The OR for the diffuse type is 27.5 (P = 4 x 10-6), as compared with an OR of 3.8 (P = 0.074) for the intestinal type. The more pronounced effect of DRB1*1601 in Hp-negative individuals, as well as the stronger effect observed for the diffuse histotype, support the notion that this allele confer susceptibility to cancer mainly in individuals with no sign of infection. The absence of serological evidence of infection in these individuals may either reflect no exposure to the bacterium, resistance to infection, immunological clearance, or elimination of Hp through mucosal abrasion.

The etiology of diffuse and intestinal types show a number of differences (29, 30, 31) . In particular, somatic mutations in p53 are less common in cells of diffuse tumors, as compared with intestinal tumors (32) . Also, inherited mutations in the E-cadherin gene are present in European multicase families with diffuse, but not with intestinal, gastric cancer (2 , 33) . Altogether, these observations indicate that inherited factors are of greater importance in diffuse as compared with intestinal tumors of the stomach. Our results, presenting a higher OR for carriers of the DRB1*1601 with diffuse tumors, also support the notion that genetic susceptibility factors are more important in this type of gastric cancer.

In summary, we have shown that alleles at two different HLA class II loci are associated with different aspects of the development of gastric cancer; one allele of DQA1 is associated with protection from infection by Hp, whereas one allele of DRB1 is associated with cancer development. The effect of DQA1*0102 has been replicated in a number of studies. Entirely novel is the strong association of the DRB1*1601 allele with cancer development. Because the effect of this allele is also observed and is actually even stronger in Hp-negative individuals, it might reflect a pathway for cancer development that is less dependent on Hp infection and most pronounced in the diffuse type of gastric cancer.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the Swedish Institute, The Beijer Foundation, The Swedish Medical Research Council, and The Uppsala Medical Faculty Fond for Undergraduate Researchers. Back

2 Both of these authors contributed equally to this work. Back

3 To whom requests for reprints should be addressed, at Department of Genetics and Pathology, Section of Medical Genetics, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Back

4 The abbreviations used are: Hp, Helicobacter pylori; CagA, cytotoxin-associated protein A; OR, odds ratio; CI, confidence interval. Back

Received 8/ 3/00. Accepted 1/21/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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