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AS689 - Helicobacter Infection and Liver Cancer Risk among African Americans and Whites in the United States

AS689 - Helicobacter Infection and Liver Cancer Risk among African Americans and Whites in the United States

[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]

Investigator Names and Contact Information

Xuehong Zhang (xuehong.zhang@channing.harvard.edu)

Introduction/Intent

In the US, liver cancer incidence has tripled since the 1980s1-3 and by 2030 is projected to be the 3rd leading cause of cancer-related death.4 Recent data shows that HBV/HCV is no longer the primary cause of liver cancer and non-viral liver cancer (i.e., HBV/HCV seronegative) is more common.5, 6 As a result, identification of additional risk factors for liver cancer beyond HBV/HCV are needed.7, 8 Emerging animal studies strongly support a role of Helicobacter pylori (H. pylori), and other Helicobacter species (i.e., H. bilis, H. hepaticus) in
liver carcinogenesis.9-12 For example, H. pylori exhibits hepatotoxicity in vitro and can induce carcinoma in the liver of animal models. H. pylori strains expressing virulence factors such as the Cytotoxin-associated gene A (CagA) and Vacuolating cytotoxin A (VacA) have demonstrated carcinogenicity in the development of gastric cancer, but related epidemiological studies assessing H. pylori and liver cancer risk are scarce.13, 14 No epidemiological study has yet investigated other Helicobacter species (i.e., H. bilis, H. hepaticus) in relation to
liver cancer risk. Interestingly, we see racial differences in both liver cancer incidence, HBV/HCV infection, and H. pylori seroprevalence.15-18 Liver cancer disproportionally affects racial/ethnic minorities. Compared to non-Hispanic whites, African Americans (AAs) have approximately two-folder higher incidence of liver cancer (e.g., 5.0 vs. 2.4 per 100,000)19 and overall H. pylori seropositivity rates in the US? (i.e., 65% vs. 40%).20 Yet, no study has investigated in AAs the relationship between Helicobacter infection and liver cancer risk.
Our long-term research goal is to decrease liver cancer morbidity and mortality by identifying new risk-factors that can be easily translated into the clinical setting. The objectives of this proposal are to identify novel risk factors for liver cancer overall and with non-viral etiology, as well as in AAs and whites. Our recent work in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial study reported a borderline significant positive association between CagA seropositivity and liver cancer risk (n=105 cases, Hazard Ratio: 1.96, 95%CI: 0.98–
3.93).14 We also recently observed in the Southern Community Cohort Study that AAs have significantly higher mean antibody levels of both VacA and CagA compared to whites.15 This finding suggests potential stronger associations between these strains with liver cancer risk in AAs but no study has yet investigated this. In this project, we propose to more comprehensively investigate the Helicobacter infection–liver cancer association by conducting a pooled prospective study that utilizes the extensive resources from 5 cohorts of
US men and women participating in the Liver Cancer Pooling Project which includes over 850,000 racially and ethnically diverse men and women with pre-diagnosis blood samples and validated covariate data who have been followed for up to 32 years. We will conduct de novo state-of-the-art assays to quantify the antibody response to 13 H. pylori proteins and to 6 proteins of H. bilis and of H. hepaticus in pre-diagnosis plasma samples from ~700 incident liver cancer cases and ~1400 healthy controls. 

Specific Aims:  

Aim 1. Determine the associations between pre-diagnostic H. pylori biomarkers and liver cancer risk in a nested case-control study of ~700 incident liver cancer cases and ~1400 healthy controls, with HBV/HCV data. We hypothesize:

1a) H. pylori seropositivity and antibody responses to 13 H. pylori proteins, especially virulence factors VacA and CagA, are associated with risk of liver cancer (~700 cases).

1b) The aforementioned associations are stronger for AAs (~200 cases) than for whites.


Aim 2. Evaluate the associations between other Helicobacter species and risk of liver cancer. We hypothesize:

2a) Antibody responses to 6 proteins of H. hepaticus and of H. bilis are associated with liver cancer risk.

2b) The aforementioned associations are stronger for AAs than for whites.


Aim 3. Evaluate the associations between Helicobacter species and risk of non-viral liver cancer (~525 cases). We hypothesize:

3a) Antibody responses to 13 H. pylori proteins, especially virulence factors VacA and CagA, as well as 5 proteins of H. hepaticus and of H. bilis are associated with non-viral liver cancer risk.