NIH/NCI – Epidemiologic Research on Emerging Risk Factors and Liver Cancer Susceptibility (R01, R21 – Clinical Trial Not Allowed)

March 9, 2018 by School of Medicine Webmaster

The following description is from the R01 version of this FOA.

Liver cancer incidence and mortality rates in the United States (U.S.) are increasing. Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer while cholangiocarcinoma (also called cancer of the bile duct) is a distant second. The established risk factors for HCC include viral hepatitis (hepatitis B [HBV] and hepatitis C viruses [HCV]), alcohol abuse, and environmental factors (e.g., smoking and aflatoxin B1). Despite this, it has been estimated that 15%-50% of HCC cases do not have evidence of viral hepatitis or heavy alcohol consumption as risk factors. For cholangiocarcinoma, the primary established etiologic risk factor is infection of Opisthorchis veverrini or Clonorchis sinensis, also known collectively as liver fluke. However, it is unclear why Americans who have never been exposed to high endemic areas of liver fluke (e.g., Thailand) would develop cholangiocarcinoma, thus suggesting that other etiologic factors exist. Collectively, there are marked disparities in liver cancer incidence, associated risk factors, and rates of progression to liver cancer by sex, age, race/ethnicity, and geographic areas.

Historically, a notable proportion of HCC has been attributed to Asian Americans and foreign-born persons that immigrated from countries where HBV is highly prevalent. Recent epidemiologic evidence suggests that non-viral factors may contribute significantly, independently, and/or in concert with viral hepatitis, to the observed increase in liver cancer incidence. These non-viral factors differentially affect different sub-populations in the U.S. These emerging non-viral factors include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, diabetes, metabolic syndrome, and others. Obesity, diabetes, and metabolic syndrome may contribute significantly to the observed rise in HCC incidence in the U.S., particularly non-Asian American populations. Moreover, with the rise in the prevalence of obesity and metabolic syndrome, NAFLD and NAFLD-associated liver diseases have been increasing among Americans. NAFLD may progress to NASH (non-alcoholic steatohepatitis), and it is estimated that 6-8% of the U.S. population have NASH. Between 70-90% of HCCs develop in people with liver cirrhosis (affecting 633,000 Americans), which is considered the penultimate step of the multistage pathogenesis of HCC. NAFLD-associated HCC can also occur in a liver without underlying cirrhosis. Although individuals with non-viral risk factors are at a lower risk for developing cirrhosis and HCC than those infected with HCV or HBV, there is greater prevalence of these underlying liver diseases in the U.S. population.

Novel hypotheses underlying liver carcinogenesis also have emerged in recent years, including the influence of the microbiome in the liver-gut axis and liver-related malignancies and the microvesicles as a potential biomarker for HCC. Environmental exposures such as ambient air pollution may contribute to the etiology of liver cancer. Additionally, there may be social and geospatial drivers that contribute to the differential incidence and mortality rates observed across US regions and populations. Because the liver’s main job is to filter the blood coming from the digestive tract, it seems likely that circulating factors in the blood, such as immunological cells and inflammatory proteins, may play a role in liver cancer risk and progression. These lines of scientific inquiry have not been fully examined.

Overall, the etiologic role of these non-viral factors associated with liver cancer is still in its early stage of investigation compared to viral-related research. Little is known about the independent role of non-viral factors in liver carcinogenesis or how they may interact with viral hepatitis or serve as a co-factor to increase susceptibility. This FOA seeks to facilitate focus on novel inquiries in liver cancer etiology using population-based studies research.

Scope of this FOA

This FOA seeks applications focusing on epidemiologic research investigating emerging and new etiologic factors and liver cancer risk in populations relevant to the United States. Applications to this FOA should include, when possible, relevant biospecimens to evaluate associated risk factors and liver cancer risk. Applications that include an investigation on viral-associated liver cancer must provide strong rationale that outlines the added innovation or new knowledge to be gained from the current evidence of viral-associated liver cancer etiology. Appropriate research applications also include those that seek to understand the interplay of multiple factors that cause liver cancer across different U.S. populations. For example, metabolic syndrome may accelerate the progression of liver disease in patients with chronic HBV infection and synergistically induce HCC development.

As noted, studies responding to this announcement should be epidemiology research, but may include aspects of basic and behavioral research, if relevant, to elucidate underlying mechanisms in humans and improve targeted prevention in high-risk populations, respectively.

Applicants could propose new projects; however, the establishment of new cohorts is not appropriate for this announcement nor will the funding of infrastructure for follow-up visits of an existing cohort be allowed. Applicants are strongly encouraged to leverage existing resources such as case-control and prospective cohort studies, and databases to utilize data and biological specimens to test the proposed hypotheses.

Proposed projects can involve primary and/or secondary data collection and analysis. Projects should involve collaborations among investigators in the U.S., when possible. Given that the etiology of liver may differ across U.S. populations, applicants may need to collaborate with international researchers, if directly relevant for the proposed research. Applicants can engage in collaborations with international partners, but the research must have direct application to the liver cancer etiologies found in U.S. populations.

Areas of research interest include, but are not limited to the following:

  • The role of non-viral risk factors (e.g., obesity, diabetes, NAFLD, NASH, metabolic syndrome, alcohol consumption) and liver cancer (HCC and non-HCC) risk;
  • The role of metabolic syndrome, obesity, diabetes, and influence of other risk factors in the progression of fatty liver, NASH, and cirrhosis to the development of liver cancer;
  • The interactions of multiple risk factors (e.g., hepatitis B, hepatitis C, HIV, metabolic syndrome, smoking, host genomics and immunologic responses) in the etiology of liver cancer;
  • The role of social, behavioral, and host factor determinants in explain differences in incidence and mortality rates for liver cancer across multiple populations;
  • Examination of novel hypotheses, risk factors, and biomarkers of liver carcinogenesis (e.g., cellular factors, telomere maintenance and length, metabolites, microbiome signatures, epigenomic alternations, gene expression and protein expression);
  • The role of pharmacologic factors (e.g. statin and metformin) and non-pharmacological supplements in liver cancer using population-based studies;
  • The role of blood circulating factors, possible biomarkers, and liver cancer development and progression; and
  • Investigation of factors that contribute to the differential risks of liver cancer between men and women
Participation in NCI’s Liver Cancer Consortium and Cancer Meetings

The PD(s)/PI(s) for the overall grant should plan to attend an NCI-sponsored meeting generally held in Washington, D.C. metropolitan area that may occur in the second year of funding. The meeting also may occur in partnership with existing consortium meeting as appropriate. The meeting will provide an opportunity for all investigators funded through this FOA and other related FOAs, including RFA-CA-17-025PAR-17-150, and PAR-17-151) to communicate, discuss the progress of their research, exchange ideas, share resources, foster collaborations, and provide input and advice to the NCI Program staff. Applicants should be willing to collaborate, when possible, with investigators funded through other liver cancer FOAs, including RFA-CA-17-025PAR-17-150, and PAR-17-151).

Deadlines:  standard dates apply


Filed Under: Funding Opportunities