Scientists make breakthrough in bile duct cancer with discovery of new gene mutations

A team of international scientists has made a significant breakthrough in understanding the cause of bile duct cancer, a deadly type of liver cancer. By identifying several new genes frequently mutated in bile duct cancers, researchers are paving the way for better understanding of how bile duct cancers develop. Their discovery is published online in Nature Genetics.

Bile Duct Cancer, or Cholangiocarcinoma, is a fatal cancer with a poor prognosis. Accounting for 10 to 25 per cent of all primary liver cancers worldwide, bile duct cancer is a prevalent disease in Southeast Asia, particularly in Northeast Thailand, which sees about 20,000 new cases each year. The high incidence in Thailand is attributed to long-term consumption of raw fish infected with liver flukes – food-borne parasites found in fish. Liver fluke infections are widespread in Northeast Thailand, where they are thought to occur in over 6 million people. Once eaten, the flukes accumulate in the bile ducts of the human host, causing constant infection and eventually the onset of cancer.

The research team was led by Bin Tean Teh, M.D., Ph.D., Director and Principal Investigator of the NCCS-VARI Translational Cancer Research Laboratory. Van Andel Research Institute (VARI) and the National Cancer Center, Singapore (NCCS) established the NCCS-VARI Translational Research Program at the National Cancer Center, Singapore in 2007. The program focuses on the biology behind varying drug responses in Asian versus non-Asian patients with specific types of cancer.

The team also included Associate Professor Patrick Tan, Associate Professor Steve Rozen (both of Duke-NUS Graduate Medical School of Singapore) and Professor Vajarabhongsa Bhudhisawasdi from Thailand's Khon Kaen University. The breakthrough came after two years of intensive research, which saw scientists from Singapore visiting the villagers in northern Thailand, and Thai researchers coming to Singapore to work in NCCS laboratories.

Professor Teh said the study will pave the way for a better understanding of the roles that newly identified genes play in the development of bile duct cancer.

“This discovery adds depth to what we currently know about bile duct cancer,” said Teh. “More important is that we are now aware of new genes and their effects on bile duct cancer, and we now need to further examine their biological aspects to determine how they bring about the onset of Cholangiocarcinoma.”

Using state of the art DNA sequencing, the researchers analysed eight bile duct cancers and normal tissues from Thai patients, and discovered mutations in 187 genes. The team then selected 15 genes that were frequently mutated for further analysis in an additional 46 cases. Many of these genes, such as MLL3, ROBO2 and GNAS, have not been previously implicated in bile duct cancers.

“With this finding we now know much more about the molecular mechanisms of the disease and we can draw up additional measures that can be taken while we identify the most appropriate treatment protocols. We are talking about the potential to save many lives in Thailand,” said Professor Vajarabhongsa Bhudhisawasdi, Director of the Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University of Thailand. “Also, this study shows that we can work closely with our counterparts in other countries and share our expertise and experience to improve the lot for the people.”

The researchers also compared the bile duct cancers to other related cancers of the liver and pancreas. Surprisingly, they found that the bile ducts cancers shared certain similarities with pancreatic cancer.

“This research provides a strong direction for future studies,” said Associate Professor Patrick Tan, faculty member of the Cancer and Stem Cell Biology Programme at the Duke-NUS. “Cholangiocarcinoma and Pancreatic Duct Adenocarcinoma appear to share more molecular similarities than earlier studies had indicated, and suggest that there are common biological pathways between the two cancers. By studying these pathways, we can then shed more light on how these tumours develop.”

Dr. Chutima Subimerb, a Thai scientist involved in the project, said she was pleased with the collaboration and to be able to participate in this health diplomacy project. “We are very privileged to be able to work alongside Prof Teh and the other scientists from Singapore. By pooling our resources we were able to make this discovery which will have very wide impact on the people, especially the poor people who have been eating the fish that they catch from the ponds and rivers in the region. I believe this is only a first step and we will see even more collaborations in time to come between our two countries in the field of scientific research.”

The research was funded by the Singapore Ministry of Health's National Medical Research Council, Millennium Foundation, Lee Foundation, National Cancer Centre Research Fund, Duke-NUS Graduate Medical School Singapore, Cancer Science Institute Singapore, Research Team Strengthening Grant, National Genetic Engineering and Biotechnology Center and the National Science and Technology Development Agency (Thailand).

About NCCS

The National Cancer Centre Singapore (NCCS) is the cancer centre dedicated to providing a holistic and multidisciplinary approach to cancer treatment and patient care. We treat almost 70 per cent of the public sector oncology cases. Through the sub-specialisation of its oncology, patients can receive the best in treatment and care. NCCS is engaged in cutting-edge clinical and translational research which has received several international acclaims. The national centre is accredited by the Joint Commission International in 2010 for quality patient care and safety.NCCS, which is set to be a global leading institution, also offers specialist training programmes to other medical institutions in Singapore and overseas.

About Duke-NUS Graduate Medical School Singapore

The Duke-NUS Graduate Medical School Singapore (Duke-NUS) was established in 2005 as a strategic collaboration between the Duke University School of Medicine, located in N.Carolina, USA and the National University of Singapore (NUS). Duke-NUS offers a graduate entry, 4-year M.D. (Doctor of Medicine) training program based on the unique Duke model of education, with one year dedicated to independent study and research projects of a basic science or clinical nature. Duke-NUS also offers M.D/PhD and PhD programs. As a player in Singapore's biomedical community, Duke-NUS has identified five Signature Research Programs: Cancer & Stem Cell Biology, Neuroscience and Behavioral Disorders, Emerging Infectious Diseases, Cardiovascular & Metabolic Disorders, and Health Services and Systems Research. For more information, please visit www.duke-nus.edu.sg.

About Khon Kaen University of Thailand

Khon Kaen University (KKU) was one of four regional universities established in 1964 as part of a decentralized development plan for higher education in Thailand. The campus is located in the Northwestern sector of Khon Kaen, just a few kilometers from the center of the city. Situated in a most attractive park, the campus covers approximately 900 hectares. From small beginnings, KKU has grown enormously and is today home to eighteen faculties, three colleges, 7 academic support centers, a hospital, a research institute and 22 research excellent centers. In addition several new institutes are currently in pipeline and will, in time, open the University's door further to the public and increase its roles, responsibilities and commitments to the region around. Currently the number of students is approximately 40,000 (including 9,800 postgraduates and about 290 students from overseas.)

About Van Andel Research Institute

Established by Jay and Betty Van Andel in 1996, Van Andel Institute is an independent research organization dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process. This is accomplished through the work of over 200 researchers in more than 20 on-site laboratories and in collaborative partnerships that span the globe. www.vai.org