AS455 - Helicobactor pylori protein-specific antibodies and colorectal cancer risk

Investigator Names and Contact Information

Meira Epplein (meira.epplein@duke.edu)

Introduction/Intent

Study Summary

Infection with Helicobacter pylori, which induces chronic inflammation in gastric mucosa, is the strongest known risk factor for gastric cancer. Recent studies suggest that H. pylori infection may also increase the risk of colorectal cancer (CRC), although these findings have been inconsistent. We recently found that participants in the Southern Community Cohort Study (SCCS), comprised of individuals recruited from community health centers that serve primarily low-income and uninsured persons in the southeastern United States, have a very high H. pylori sero-prevalence. In fact, both African Americans and whites in the study have H. pylori sero-prevalences that rival developing countries (89% and 69%, respectively). Due to this high prevalence, outcomes of public health importance that may be associated with H. pylori infection need to be examined, as there could exist the potential for cost-effective prevention through targeted H. pylori eradication therapy.

Two recent meta-analyses found significant 40% to 50% increased odds for CRC among those individuals with a current or past H. pylori infection. However, the majority of the studies surveyed did not investigate H. pylori sub-type. It is known that as H. pylori has evolved over 50,000 years to live in the stomach, the bacteria have become highly diverse genetically. Our recent research, which utilized a nested case-control design within the SCCS and assessed H. pylori status through multiplex serology, demonstrated that sero-positivity to any of five specific H. pylori proteins was associated with a significant 60-80% increase in the odds of CRC risk. For colon cancer alone, these associations were stronger, so that sero-positivity for any of these five proteins was associated with a statistically significant greater than two-fold increased risk for colon cancer, most prominently for the known virulence factor, vacuolating cytotoxin (VacA) (OR for VacA sero-positivity, 2.24). The association of VacA sero-positivity was particularly strong for cancer diagnosed at late stage (OR, 5.67), among younger (<55 y) individuals (OR, 3.48), and for cancer of the right colon (OR, 3.13). Furthermore, there was a strong positive dose-response across increasing quartiles of *H. pylori *protein-specific antibody level.

These findings are particularly relevant as although in the US there has been an overall decline in incidence of CRC, it is still the third most common and third most deadly cancer and there is evidence that CRC incidence is increasing among both men and women less than 50 years of age, who are also more likely to be diagnosed with late-stage disease. Thus, our pilot results of significant, dose-response associations between levels of antibodies to the H. pylori protein VacA and CRC, and specifically with cancer of the right colon and colon cancers diagnosed at late stage and young age, are new, and require replication in large, prospective cohort studies to determine the consistency and generalizability of the results, and to establish a framework to inform future studies that will define the mechanisms underpinning the associations. Additionally, based on the effect modification by H. pylori status suggested in the literature for the association of aspirin use and gastric cancer risk and the evidence that aspirin may directly reduce the carcinogenic effect of H. pylori, and the protective effect of aspirin on CRC risk, it would be of great scientific and public-health interest to determine whether aspirin use modifies the association between H. pylori protein-specific infection and risk of CRC.

To further our understanding of the H. pylori–colorectal cancer association, this project will:

Aim 1: a) Evaluate the H. pylori subtype-specific association with CRC risk among over 4,000 cases and 1:1 matched controls in a consortium of prospective studies, including the Multiethnic Cohort Study, the Women's Health Initiative, the Prostate, Lung, Colorectal and Ovarian Screening Study, the Health Professionals Follow-up Study and Nurses' Health Study, Campaign Against Cancer and Stroke, the NYU Women's Study, the Cancer Prevention Study-II, the Physicians' Health Study, and additional new incident cases in the Southern Community Cohort Study;

b) Assess the strength of the association and the variation by histologic site, stage, and age at onset; and

c) Investigate whether the association differs by time from antibody status assessment to cancer diagnosis.

Aim 2: Investigate whether the association between specific H. pylori proteins and risk of CRC is modified by regular aspirin use. Specifically, to assess whether reductions in CRC risk associated with regular aspirin use are greater in the presence of virulent strains of H. pylori.