Roles of Helicobacter pylori infection, host genetic variation, and other environmental exposures in gastric carcinogenesis

Sammanfattning: Despite a general declining secular trend of incidence in most parts of the world, stomach cancer is still a major cause of cancer-related death worldwide due to its poor prognosis. Although Helicobacter pylori (H. pylori) infection is an established risk factor for stomach cancer, the true magnitude of the association is still not determined. Besides H. pylori infection, some other factors including host genetic variation and environmental exposures might to play a role in gastric carcinogenesis. As acquisition of the infection almost invariably occurs before adulthood, the serostatus at age 16-40 should best reflect the lifetime occurrence of the infection. Study I is a case-control study nested within a historic cohort approximately of 400 000 individuals. These individuals donated sera before age 40 years to either of two large Swedish biobanks between 1967 and 2006 and were linked to complete nationwide registers. In total 59 incident cases of stomach adenocarcinoma (41 non-cardia tumours) were confirmed. The risk of non-cardia stomach adenocarcinoma among subjects with antibodies against both H. pylori cell surface antigens and CagA, relative to those who were seronegative, was 48.5 (95% CI, 5.8-407.4). This result provides strong evidence that H. pylori infection is a much stronger risk factor for non-cardia stomach adenocarcinoma than initial reports indicated. The study II is composed of a population-based case-control study based in five Swedish counties and a hospital-based case-control study conducted at eight Swedish hospitals which provided a combined total of 351 gastric cancer cases and 539 controls for analysis. The IL1B- 31, IL1B-511, and IL1B+3954 biallelic polymorphisms were genotyped. The risk of gastric cancer was unrelated to genotype in all of the studied polymorphic loci, and the absence of association was also evident when the population-based and hospital-based case-control studies were analyzed separately. These results do not support the hypothesis that human genetic polymorphisms linked to IL-1beta production are associated with the risk of gastric cancer. Study III is a population-based case-control study conducted in Warsaw, Poland, during 1994- 1996. This study provided 273 stomach cancer cases and 377 controls in which 6, 8, and 14 tagSNPs in MUC1, MUC5AC, and MUC6 genes, respectively, were genotyped. Each of the six tagSNPs tested across the MUC1 region showed association with an increased risk of stomach cancer. Carriers of the haplotype ACTAA rare alleles of rs4971052, rs4276913, rs4971088, rs4971092, and rs4072037 had an approximate two-folded increase in risk (OR 1.93, 95% CI, 1.49-2.48) compared to the referent haplotype. Out of 8 tagSNPs across MUC5AC region, only the minor allele of rs868903 was significantly associated with an increased risk of stomach cancer (OR 1.80, 95% CI, 1.22-2.63). No significant association was found in tagSNPs across MUC6 genes. In conclusion, some common variations in MUC1 and MUC5AC genes likely contribute to an elevated risk of stomach cancer. Study IV, was based in the JPHC Prospective Study which is composed of 36 745 subjects aged 40 to 69 years, who responded to a baseline questionnaire and provided blood during 1990-1995 and were subsequently followed until 2004. Plasma levels of carotenoids in 511 gastric cancer cases and 511 matched controls were measured. The plasma level of beta-carotene was inversely associated with risk of gastric cancer (compared with lowest quartile: OR 0.63, 95% CI, 0.31-0.75; OR 0.48, 95% CI, 0.31-0.75; and OR 0.46, 95% CI, 0.28-0.75, for the 2nd, 3rd and 4th quartile respectively). Inverse associations were evident in men for alpha-carotene and betacarotene, but not in women who had relatively higher plasma levels compared with men. No statistically significant association between lutein/zeaxanthin, lycopene, retinol, alpha- or gamma- tocopherol with gastric cancer was found. These findings suggest that those who have low plasma levels of alpha- and beta-carotene have an increased risk of gastric cancer.