Over 40% of US liver cancer cases are not attributable to known risk factors such as HBV/HCV infections, aflatoxin, excessive alcohol intake, smoking, and metabolic disorders, and likely stem from unidentified exogenous exposures. One highly ubiquitous environmental contaminant are per- and polyfluoroalkyl substances (PFASs): a large family of man-made organofluorine compounds that are very persistent in both the environment and human body. We are all exposed to PFASs on a daily basis. The liver is a target organ of PFASs, and emerging evidence from laboratory and observational studies is converging to strongly support the scientific premise that higher population exposure to PFASs increases the risk of liver cancer. For example, low dose background PFAS exposure in the general population is correlated with altered liver function; PFAS can accumulate in human liver tissue and also cause liver cancer in experimental studies via various mechanisms; and retrospective mortality cohort studies report that workers occupationally exposed to PFASs experienced significant increases in mortality due to liver cancer. However, no study has yet directly investigated the relationship between PFAS exposure and risk of liver cancer in the general US population.

Our long-term research goal is to decrease liver cancer morbidity and mortality. The objective of this proposal is to determine the relationship between PFAS exposure and liver cancer. In recent work in the Nurses’ Health Studies and Health Professionals Follow-up Study, we found that (1) obesity, weight gain, and diabetes are significant, independent risk factors for liver cancer, (2) plasma levels of PFASs in the NHS cohort are comparable with those in the general US population, highly reproducible, and (3) higher plasma levels of PFAs were associated with higher risk of diabetes and weight gain. To expand on these findings, we now propose to further investigate the relationship between PFASs and liver cancer risk by conducting a prospective nested case-control study utilizing the extensive resources from the PLCO study. Our specific aims are to:

Aim 1. Characterize the associations between circulating levels of PFASs and liver cancer risk in a nested case-control study of 120 incident liver cancer cases and 240 healthy controls. We hypothesize that:
Higher circulating levels of PFASs, especially PFOA and PFOS that showed an increased risk of liver cancer in experimental studies, are associated with higher risk of developing liver cancer.

Aim 2. Determine the associations between liver cancer risk and environmental PFAS exposure by mixture patterns. We hypothesize that: A synergism presents among the PFAS mixtures on liver cancer risk.

Aim 3. Determine whether risk factors of liver cancer (obesity and diabetes) modify or mediate the relationship between PFAS and elevated risk of liver cancer. We hypothesize that:
Baseline obesity and diabetes modify this relationship; and obesity and diabetes partially mediate the relationship between PFAS exposures and liver cancer risk.

The study will provide the first line of evidence liver cancer associated with PFAS exposures in the general US population.

Xuehong Zhang (Harvard Medical School and Brigham and Women's Hospital)
Katherine McGlynn (NCI)
Qi Sun (Harvard Chan School)
Edward Giovannucci (Harvard Chan School)
Tongzhang Zheng (Brown University)
Simin Liu (Brown University)
Michelle Lai (Harvard Medical School)
Staci Sudenga (Vanderbilt University)
Brent Coull (Harvard Chan School)
Liming Liang (Harvard Chan School)
Lesley Tinker (Fred Hutch Cancer Center)