The main aim of this study is to further our understanding of the H. pylori colorectal cancer association. To do this, we propose to first attempt to replicate our pilot findings of an H. pylori subtype-specific association with colorectal cancer risk in a consortium of prospective studies, including the Multiethnic Cohort Study, the Cancer Prevention Studies, the Health Professionals Follow-up and Nurses Health Study, and the NYU Womens Study, and to assess variation in the association by histologic site, stage, and age at onset. Secondly, we will seek to validate the H. pylori subtype-specific association with colorectal cancer risk among the screened participants of the Prostate, Lung, Colorectal, and Ovarian Screening Trial, and to investigate the association among those individuals with two or three blood draws at different time points prior to cancer diagnosis to assess changes in the association over time. Our third and final aim is to examine the potential mechanistic pathway between H. pylori strain-specific infection and colorectal cancer by analyzing the associations with gastric atrophy, measured using pepsinogen levels (among all participants in Aims 1 and 2), gastrin, measured as serum gastrin levels (for those participants with fasting blood draws), and the end product of the COX-2 pathway, urinary prostaglandin E2 (among the members of the cohorts with available urine samples). We will assess whether these measures of potential intermediate variables add predictive value to the H. pylori strain-specific model. We hypothesize that infection with a VacA-positive strain of H. pylori is associated with an increased risk of colon cancer in the general US population, and that this association is strongest for early-onset, advanced-stage disease. We also hypothesize that high gastrin levels will add predictive capability to the model of H. pylori antibodies and colorectal cancer risk, and will suggest that only VacA-positive H. pylori-infected individuals who also have high gastrin levels are at specifically increased risk of colon cancer. We expect to also see a similar association between a low pepsinogen I:II ratio and for high PGE-M levels. Finally, we believe that the association of VacA antibody levels and colorectal cancer risk could strengthen as onset of disease nears (possibly as a marker of increased host inflammation) or the association could weaken as onset of disease nears, as the H. pylori bacterial load could decrease as simultaneously gastrin levels increase. The understanding of this association, through the use of the PLCOs unique resource of serial samples prior to diagnosis, will help to put the pieces together that will then provide the opportunity for the development of an H. pylori biomarker for colorectal cancer risk.

William J. Blot (Vanderbilt University)
Meira Epplein (Duke University)