AS694 - Circulating metabolites as novel risk biomarkers for gastric cancer: a large multi-center prospective investigation

Investigator Names and Contact Information

Introduction/Intent

Despite the decline in incidence, gastric cancer remains the 5th most common and the 3rd leading cause of cancer deaths worldwide. Improving the current knowledge on the disease etiology and developing tools to distinguish high-risk subgroups from general population is of particular importance in mitigating the health burden associated with gastric cancer. Finding blood biomarkers serving both purposes represents a long interest in cancer research due to the non-invasive nature. Herein, we propose a multi-center investigation on gastric cancer risk using untargeted and targeted metabolomics techniques. Multiple large cohorts will participate in this collaboration by contributing pre-diagnostic blood samples and epidemiological data. The proposed research is expected to make a contribution to a deeper understanding of the disease etiology and identify novel metabolite biomarker for gastric cancer risk assessment.

SPECIFIC AIMS

Despite the decline in incidence, gastric cancer remains as a common and deadly cancer worldwide. It is the 5th most common and the 3rd leading cause of cancer deaths, with an estimated one million new cases and 783,000 deaths in 2018[1]. Gastric cancer also imposes an important health threat in US as an estimated 27,600 new cases will be diagnosed in 2020[2]. Of note, the 5-year relative survival is merely 20-30% for the patients with a notable exception for Japan and South Korea[3-6]. Helicobacter pylori (H. pylori) infects nearly 50% of the global population, which is the most recognized risk factor for gastric cancer[7]. It has been estimated that H. pylori infection may contribute to the development of approximately 90% of non-cardia gastric cancer[7]. Other major risk factors include sex (male), smoking, and alcohol consumption, etc.[8].

Identifying blood biomarkers for cancer risk assessment and a better understanding of cancer etiology represents a long interest in cancer research due to the non-invasive nature. For example, H. pylori is considered the most important risk factor for gastric cancer. A panel of human antibodies to H. pylori recombinantly expressed fusion proteins were developed for characterizing high-risk subgroups among general populations[9-11]. We previously showed that subjects with a seropositivity status had a 2- to 4-fold risk of developing incident gastric cancer compared to their counterparts, supporting the etiological role of H. pylori infection[10]. However, with the rate of H. pylori infection decreasing over the years, new biomarkers are in need to aid the conventional ones especially among those who lack the traditional risk factors of the disease. Since reflecting the state of the human body in a quantitative and comprehensive way, blood metabolome may fulfill this need, taking the advantage of its non-invasive nature.

Specific Aim 1: We hypothesize that perturbation of blood metabolome is associated with gastric cancer risk across populations with different racial background. To test the hypothesis, we will establish a multi-center international study for gastric cancer with a focus on metabolomics. In addition to WHI, we have invited the Shanghai Women’s Health Study (SWHS), the Shanghai Men’s Health Study (SMHS), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), European Prospective Investigation into Cancer and Nutrition (EPIC), and the NYU Women’s Health Study (NYUWHS) to participate in this study. We will perform assays to profile circulating metabolites in ~1,200 cases and 1,600 controls using a global LC-MS platform. We also request information on H. pylori infection or will generate the data if not available. We expect the research proposed in this aim will facilitate a better understanding of gastric cancer etiology and identify biomarkers independent of H. pylori infection and other major risk factors for risk assessment. We will reserve 20-30% of samples from each participating cohort for validation purpose.

Specific Aim 2: To evaluate the inter-relationships of known lifestyle risk factors, blood metabolites, and gastric cancer risk. We will use the metabolomics data described in Aim 1 and the exposure data collected in the parent cohort studies for the proposed analyses. Smoking, alcohol drinking, salt-preserved foods are known risk factors for gastric cancer, although the mechanisms are not fully understood. We will investigate the relationship between these lifestyle factors and metabolites and specially interrogate the associations of smoking/alcohol/food-related metabolites with gastric cancer risk individually and as a group. The proposed research will help clarify the potential mediating effects of metabolites on the associations of the traditional risk factors with gastric cancer, assisting in gaining new knowledge on potential mechanisms related to the cancer occurrence.

Specific Aim 3: Explore group specific associations and interaction effects by sex, H. pylori infection, and dietary intakes (tea/coffee intake). We conducted a pilot study in the SWHS/SMHS and identified several notable interactions for metabolites and sex/H. pylori infection/tea intake. We propose to further investigate the potential subpopulation-specific associations (women vs men, HP infected vs HP free, tea/coffee drinker vs non-drinker etc.) and interactions. The proposed research will not only help elucidate the disease etiology but also identify biomarkers specific to subpopulation who do not have the traditional risk factors for gastric cancer.