Scientists uncover a major gene loss that leads to liver cancer

Metastatic hepatocellular carcinoma Credit: Wikimedia commons
  • First-in-the-world discovery that a loss of the GATA4 gene is a common key reason for the development of liver cancer, the second leading cause of cancer deaths worldwide
  • 7 in 10 liver cancer patients worldwide exhibit GATA4 gene deletion; affects 1 in 2 liver cancer patients in Singapore
  • This discovery has major implications for developing new drugs through a new pathway in liver cancer

A clinician scientist-led research team from the National Cancer Centre Singapore (NCCS) and their US partner from the Cleveland Clinic has led to an important discovery that the GATA4 gene, which contributes to normal liver develoment, is commonly deleted in liver cancer.

According to the Singapore Cancer Registry (2011-2015), liver cancer is the third most common cause of cancer deaths in men and fourth most common for women in Singapore.

The study (titled GATA4 loss-of-function in liver cancer impedes precursor to hepatocyte transition) is the first-in-the-world study to identify that GATA4 is a key gene that guards the liver against cancer.

Loss of this gene in liver affects the normal liver development and exposes the liver to significant risk of cancer development. GATA4 is a necessary gene for normal liver development and growth. It was discovered that the loss of GATA4 results in abnormal cellular machinery and division, caused unstable cells with wide-ranging negative effects.

Associate Professor Toh Han Chong, deputy director and senior consultant at National Cancer Centre Singapore, is the leader and co-senior author of the study. A/Prof Toh said: “In the last many decades of liver cancer research, the molecular understanding of this disease has not led to many therapies which impact on patient survival. We hope that this new finding will light up a treatment path towards greater benefit and outcomes for liver cancer patients.”

Professor Yogen Saunthararajah, co-senior author of the study, staff clinician, and professor at Cleveland Clinic, USA, said: “Liver cancer, or hepatocellular carcinoma (HCC), is the world’s second leading cause of cancer death. For the past decade or so, there has only been one drug approved for the treatment of liver cancer, which is sorafenib. If we are to develop new and more effective treatments, a crucial first step is to understand how the instructions for liver assembly go wrong and make liver cancer instead.”

The team is the first group to report the major roles of GATA4 loss in liver cancer. In normal liver, GATA4 is essential in gathering and regulating different necessary factors to execute the correct liver development programme. Loss of GATA4 in liver will result in uncontrolled growth of liver cells, leading to diseases, such as fatty liver, obesity, and cancer development.

NCCS Research Fellow, Dr Timothy Shuen, is co-first author of the study. Dr Shuen explained: “Losing the GATA4 gene is like losing one of the main guardians of the liver. The liver can no longer be protected from stress and the normal liver machinery is damaged.”

A/Prof Toh has just recently been awarded the National Medical Research Council (NMRC) clinician scientist – individual research grant 2016 and the NMRC National Senior Clinician Scientist Award 2017. These grant and award provide funding and opportunity to dive much deeper into vital mouse-to-man studies on how GATA4 loss leads to such major instability to normal cells and its surrounding environment. The grant also supports the testing of novel new therapies to overcome this key genetic defect.

The study was published in the Journal of Clinical Investigation (JCI) today.