Viral exposure signatures in hepatocellular carcinoma
Principal Investigator
Name
Katherine McGlynn
Degrees
Ph.D.,M.P.H.
Institution
National Cancer Institute
Position Title
Senior Investigator
Email
About this CDAS Project
Study
PLCO
(Learn more about this study)
Project ID
2021-0015
Initial CDAS Request Approval
Jul 21, 2021
Title
Viral exposure signatures in hepatocellular carcinoma
Summary
Liver cancer, the third leading cause of global cancer mortality, has one of the most rapidly increasing incidence rates in the U.S. Between 1999 and 2006, liver cancer experienced the second greatest annual percent increase in incidence (2.3%) and the single greatest annual percent increase in mortality (2.0%) of all major cancers. These increases are particularly notable as liver cancer has the third worst prognosis among major cancers, with a 5-year survival rate of less than 15%. It is estimated that approximately 5% of cancer deaths among men and 3% among women are due to liver cancer, making it one of the top ten causes of cancer mortality.
The dominant histological type of liver cancer is hepatocellular carcinoma (HCC). Major risk factors include hepatitis B virus (HBV), hepatitis C virus (HCV), aflatoxin, alcohol, smoking, obesity, diabetes, and fatty liver disease. Collectively, however, these factors only account for approximately 60% of HCC. Thus, the examination of other factors is clearly warranted. One such factor may be a person’s viral exposure history.
Viruses are known to affect human health by altering host immunity, thus contributing to the pathogenesis of chronic diseases, including cancer. Diverse pathogenic and non-pathogenic viruses may interact with each other, and with their host, to shape host immunity, which may then alter the host response to other insults. As a result of many virus-human interactions over time, each person has a viral exposure signature (VES), which may be different in persons who develop in HCC and persons who do not. Until recently, it has been challenging to examine total VES as the presence of antibodies against each virus had to be examined independently. The development of technology to examine antibodies against all known human viruses simultaneously, however, has revolutionized VES studies, making them much more tractable.
Only one prior study has examined the VES hypothesis in HCC. That study, led by a collaborator on the proposed project, used a synthetic virome technology, VirScan, to identify a unique VES associated with HCC. The VES consisted of the epitopes of 61 viral strains, 18 of which were positively associated with HCC and 43 of which were negatively associated. Major positive associations with HCC included HCV, CMV, HDV, and influenza H1N1 and H3N2. Major negative associations included RSV and rhinovirus-23. The investigation also examined whether the host’s genetic background was associated with the host’s VES. Significant differences in 3 SNPs (rs34725101 in RHOA, rs4483229 in EPB41L4B and rs16960234 in CDH13) between persons with high- and low-VES scores were identified. While these results were intriguing, the study had several limitations including that it was case-control in design and the participants’ HCV and HBV serological status were unknown. Neither limitation exists in the PLCO population as it is a prospective study in which HBV and HCV status have been determined for many of the samples. In addition, a GWAS of the entire PLCO has been completed, making it an ideal population for the proposed research.
The dominant histological type of liver cancer is hepatocellular carcinoma (HCC). Major risk factors include hepatitis B virus (HBV), hepatitis C virus (HCV), aflatoxin, alcohol, smoking, obesity, diabetes, and fatty liver disease. Collectively, however, these factors only account for approximately 60% of HCC. Thus, the examination of other factors is clearly warranted. One such factor may be a person’s viral exposure history.
Viruses are known to affect human health by altering host immunity, thus contributing to the pathogenesis of chronic diseases, including cancer. Diverse pathogenic and non-pathogenic viruses may interact with each other, and with their host, to shape host immunity, which may then alter the host response to other insults. As a result of many virus-human interactions over time, each person has a viral exposure signature (VES), which may be different in persons who develop in HCC and persons who do not. Until recently, it has been challenging to examine total VES as the presence of antibodies against each virus had to be examined independently. The development of technology to examine antibodies against all known human viruses simultaneously, however, has revolutionized VES studies, making them much more tractable.
Only one prior study has examined the VES hypothesis in HCC. That study, led by a collaborator on the proposed project, used a synthetic virome technology, VirScan, to identify a unique VES associated with HCC. The VES consisted of the epitopes of 61 viral strains, 18 of which were positively associated with HCC and 43 of which were negatively associated. Major positive associations with HCC included HCV, CMV, HDV, and influenza H1N1 and H3N2. Major negative associations included RSV and rhinovirus-23. The investigation also examined whether the host’s genetic background was associated with the host’s VES. Significant differences in 3 SNPs (rs34725101 in RHOA, rs4483229 in EPB41L4B and rs16960234 in CDH13) between persons with high- and low-VES scores were identified. While these results were intriguing, the study had several limitations including that it was case-control in design and the participants’ HCV and HBV serological status were unknown. Neither limitation exists in the PLCO population as it is a prospective study in which HBV and HCV status have been determined for many of the samples. In addition, a GWAS of the entire PLCO has been completed, making it an ideal population for the proposed research.
Aims
1) Examine whether there are significant difference between the VES of HCC cases and controls
2) Examine whether whether there are significant differences in cases and controls beyond HCV and/or HBV status
3) Examine whether there are significant associations between the host’s genetic background and the host’s VES
Collaborators
Katherine McGlynn (National Cancer Institute)
Joshua Sampson (National Cancer Institute)