Ground-breaking research from the Duke-NUS Genomic Platform
The in-house genomic platform at Duke-NUS has resulted in several discoveries led by scientists at Duke-NUS and has strengthened research collaborations with teams in and beyond Singapore.
East Asian gene variant discovered to cause resistance to cancer targeted therapy
Without his DNA helix bowtie, the gingerbread in the middle realizes he has the BIM deletion polymorphism, and hence less likely to respond well to medication.
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Duke-NUS and SGH cancer researchers, Drs. Ong Sin Tiong and Charles Chuah, together with a multinational team, have identified a variation of the BIM gene that explains why some patients fail to benefit from highly-effective cancer drugs called tyrosine kinase inhibitors (TKIs).
In the study, which was led by Dr. Ong, an Associate Professor in the Cancer and Stem Cell Biology Signature Research Program at Duke-NUS and Division of Medical Oncology at Duke University Medical Center in the US, genome sequencing technology was used to look for structural changes in the DNA of patient samples. Using this approach, they discovered the BIM gene variant among patients who were resistant to TKIs but not in those who were sensitive. Interestingly, the BIM gene variant was commonly found (~15% incidence) in individuals of East Asian descent (Chinese, Japanese, and Koreans), but was completely absent in Caucasians and Africans. The study, published online in Nature Medicine on March 18, is significant, said Dr. Ong, "Because knowing about the effects of the gene variant allows for better identification of patients who are more likely to respond poorly to TKI therapy. In this way, we will be able to personalize therapy for these patients to avoid ineffective therapies that could be toxic and expensive, and test out new strategies to prevent TKI resistance from developing."
Having identified the mechanism by which the BIM variant caused drug resistance, the team predicted that another class of cancer drugs, called 'BH3 mimetics', would be able to overcome it. Dr. Ong said: "When the BH3 mimetic drugs were added to TKIs in cancer cells with the BIM gene variant, we were able to overcome the resistance conferred by the gene. Our next step will be to bring this to clinical trials with patients."
The genomics platform in action
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Critical stomach cancer genes identified
The identification of hundreds of mutant genes in stomach cancer may help doctors improve the customization of cancer treatments. The study, led by Duke-NUS in collaboration with the National Cancer Center Singapore (NCCS) and international partners, discovered the gene mutations by analyzing both normal and tumour tissues from stomach cancer patients using DNA sequencing technology. Out of the 18,000 genes studied, they found more than 600 genes that were previously unknown to be mutated in stomach cancer. Two genes called FAT4 and ARID1A were found to be particularly significant. These genes were mutated in 5 and 8 per cent of stomach cancers, respectively. According to Assoc. Prof. Patrick Tan, the senior author of the study from the Cancer and Stem Cell Biology Program at Duke-NUS and who is affiliated with the Cancer Science Institute of Singapore, and A*STAR's Genome Institute of Singapore, this newfound knowledge may help lead to more effective treatment of stomach tumors and other cancers. In addition, senior co-author Assoc. Prof. Steven G. Rozen, Ph.D., who heads the Computational Systems Biology and Human Genetics Laboratory in Duke-NUS, noted, "This technology allows us to read the DNA sequence of the protein-coding genes in each cancer genome for less than US$2,000 (SGD$2,500), an incredibly low price." The findings were published online on April 8 in Nature Genetics.
New gene mutations implicated in bile duct cancer
Prof. Teh Bin Tean, lead researcher for the breakthrough in bile duct cancer gene mutation
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Researchers from Duke-NUS, the National Cancer Center of Singapore (NCCS) and Khon Kaen University in Thailand have used state-of-the-art genomic technologies to discover that new gene mutation that occur in bile duct cancers, or cholangiocarcinoma. Researchers analysed eight bile duct cancers and normal tissues from Thai patients, and discovered mutations in 187 genes, including genes such as MLL3, ROBO2 and GNAS, that have not been previously implicated in bile duct cancers. The researchers also compared bile duct cancers to other related cancers of the liver and pancreas and found that the bile ducts cancers shared similarities with pancreatic cancer.
This finding, said lead researcher Professor Teh Bin Tean, Director and Principal Investigator of the NCCS-VARI Translational Cancer Research Laboratory at the NCCS and professor at Duke-NUS, paves the way for better understanding on how bile duct cancers develop. "This discovery adds depth to what we currently know about bile duct cancer. 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." The discovery was published on May 6 in Nature Genetics.
Bile duct cancer is a fatal form of cancer that accounts for 10 to 25 per cent of all primary liver cancers worldwide and is prevalent in Southeast Asia, particularly Northeast Thailand. The cancer is caused by long-term consumption of raw fish infected with liver flukes (a type of parasite found in fish). When eaten, the flukes accumulate in the bile ducts of the human host, causing constant infection and the onset of cancer.
For more information regarding DGBF services and collaborations, please contact Assoc. Prof. Patrick Tan at gmstanp@duke-nus.edu.sg or Ms Angie Tan at angie.tan@duke-nus.edu.sg. Some DGBF equipment was purchased by a grant from the Cancer Science Institute of Singapore.
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