Grant Number:	3R01CA255809-04S1 Interpret this number
Primary Investigator:	Yuan, Jian-Min
Organization:	University Of Pittsburgh At Pittsburgh
Project Title:	Differential Risk Factors for Hepatocellular Carcinoma in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Patients of Native Hawaiians Compared with Us Whites
Fiscal Year:	2024

Cancer health disparities remain in the US health care system. The incidence rate of liver cancer was 8 times in American Samoans and 2-3 times in Native Hawaiians compared with non-Hispanic whites (NHW) (https://minorityhealth.hhs.gov/). The underlying reasons for this large variation in liver cancer between Native Hawaiians/Other Pacific Islanders (NHPI) and NHW are not completely understood. It is generally believed that lifestyle factors, cultural barriers, and disparate exposures to carcinogens and pathogens may contribute to the liver cancer disparities. In this supplemental grant application, we propose to expand our original cohort of high-risk individuals for liver cancer in Western Pennsylvania, most of whom are NHW, to recruit and establish a cohort of NHPI individuals at high risk for liver cancer, through an inter-institutional collaboration. The liver is an organ that is constantly exposed to a wide range of immunomodulators, environmental toxins, and gut microbial metabolites through the portal vein. To ensure upkeep of immune tolerance to self and foreign antigens, the liver has a unique immunotolerance mechanism. Heightened immunotolerance or immune permissive microenvironment may create a setting with compromised immunosurveillance that promotes the tumor development and growth in the liver. The gut microbiota can produce large quantities of metabolites such as secondary bile acids that have genotoxic and tumor-promoting effect. The gut dysbiosis due to obesity and other metabolic diseases, which are underlying conditions for non-alcoholic fatty liver, alters the metabolism, synthesis, and transport of bile acids, resulting in the change of bile acid pool size and characteristics. The altered bile acids profile can elicit inflammation and cause liver injury, leading to fibrosis and cirrhosis, and eventually hepatocellular carcinoma. We propose prospectively enroll at NHPI patients with non-alcoholic fatty liver disease. All study participants will be longitudinally followed up for the occurrence of liver cancer and end-stage liver disease. The specific aims are to determine if immunosuppressive cytokines, altered bile acid profiles, and the gut dysbiosis have significant impact on the risk of developing liver cancer and end-stage liver disease. Furthermore, we will integrate these data with the similar study in NHW in Western Pennsylvania and assess the differential associations for immunosuppressive cytokines, altered bile acid profiles, and the gut dysbiosis with liver cancer risk between the two study cohorts. The findings, if prove our hypotheses, will provide much needed scientific evidence for our understanding the liver cancer disparity between NHPI and NHW populations. These finding will help develop effective and unique strategy for management and surveillance for NHPI individuals at high risk for developing liver cancer and other end-stage liver disease.





None. See parent grant details.