The Genetic Basis of Sex Differences in Liver Cancer

Principal Investigator: LAU, YUN-FAI C
Program: PRCRP
Proposal Number: CA150248
Award Number: W81XWH-16-1-0488
Funding Mechanism: Idea Award with Special Focus
Partnering Awards:
Award Amount: $613,200.00


This project focuses on the male predominance of liver cancer, a new cancer for the Fiscal Year 2015 Peer Reviewed Cancer Research Program Topic Areas. Results of the project will advance the Military Relevance Focus Areas in militarily relevant risk factors associated with cancer and gaps in cancer screening, early detection, diagnosis, treatment, and/or survival preferentially affecting military members and Veterans.

Liver cancer is a deadly cancer worldwide. Survival rates are very low if the cancer is diagnosed at late stages. Risk factors include chronic hepatitis virus infections, alcoholism, toxic exposure, drug abuses, and male gender, which are highly prevalent among military members and Veterans. Accordingly, Veterans are five times more susceptible to liver cancer than the American general population. Significantly, there are four times more men than women having liver cancer. At present, the male predominance in liver cancer is a medical mystery. Some studies suggest that female hormones protect women and the male hormones promote liver cancer in men. These concepts have dominated the research field for years. Yet, little progress has been made in advancing the screening, diagnosis, and prognosis of the disease. We challenge the hormonal paradigms and suggest that there are significant genetic components of the male predominance of the disease, particularly genes on the man-only Y chromosome. Men and women are genetically identical except their sex chromosomes, i.e., X and Y chromosome. Men have an X and a Y while women have two X chromosomes. So if there is a cancer gene on the Y chromosome, only men will be susceptible while women will not be affected. Indeed, there is a cancer gene on the Y chromosome, called TSPY. It is a specialized factor for sperm production in the testicles, but if it is abnormally expressed in other types of cells, it behaves as a cancer gene, promoting cancer development. Indeed, three independent studies, including ours, have clearly demonstrated the activities of this male-specific cancer gene in liver cancer of male patients. Patients with this cancer gene active in their tumors have much poorer survival rates than those without. Among the various types of cancers, liver cancer has the most patients with this cancer gene active in their tumors. This observation correlates well with the fact that liver cancer has the most disproportionately high male preference among its patient populations. Accordingly, we hypothesize that this Y chromosome cancer gene could have a positive effect(s) on liver cancer development, thereby contributing to the male bias in this type of cancer.

The proposed research plans to validate the male-specific cancer gene as diagnostic and predictive marker in liver cancer in a comprehensive study on a set of patients whose tumor grades and survival information are known. Once established, we plan to use the information in a pilot study in diagnosing and predicting the outcomes of liver cancer patients undergoing treatments at the Veterans Affairs Hospital in San Francisco. We will explore some non-invasive means to detect the cancer gene products in the sera of these patients and to determine if such information can be used as diagnosis and monitoring for relapses in the patients. We will characterize the properties of the male-specific cancer gene in cultured liver cancer cells and evaluate its responses to a specific drug against its actions in a tumor model in mice.

Since most of the active duty military members and Veterans are men, this system will have immediate impact to liver cancer prevention, screening, and diagnosis among them. Success in non-invasive means to detect this male-specific cancer gene products in the sera of liver cancer patients will provide a powerful and effective strategy to screen high-risk groups on a regular basis for signs of the disease and to monitor the clinical progression of liver cancer patients, before and after resection surgery, and to detect relapses in follow-up clinic visits. Efficient and economical screening kits could be established within a couple of years, based on this male cancer gene biology, and the above procedures can potentially be simplified as a routine blood test. Understanding the actions of the male-specific cancer gene in liver cancer will provide critical information for developing individualized treatments of the male military and Veterans patients, as well as those in the general American population. Patients positive for this cancer gene will be treated with specific drugs against its actions or as an add-on to conventional treatment while those negative for it will be treated differently with other means. This type of treatment plans constitutes a critical component of the precision medicine for effective and personalized clinical management of liver cancer, especially among the high-risk groups, including many of male military members and Veterans.