Researchers have the stomach for cancer
May 2012
by Kelsey Kaustinen  |  Email the author


SINGAPORE—Hundreds of novel genes that are mutated in stomach cancer have recently been identified, providing a much-needed update on the second most lethal cancer in the world. The research, done by an international team of researchers led by members from Duke-NUS Graduate Medical School (Duke-NUS) in Singapore and the National Cancer Center Singapore (NCCS), appeared online April 8 in Nature Genetics.  
"Our study is one of the first gastric cancer studies to investigate the vast majority of human genes at the single nucleotide level," Prof. Teh Bin Tean, director of the NCCS-VARI Translational Research Laboratory at NCCS and senior co-author of the study, said in a press release. "We screened 18,000 human genes and identified over 600 genes that were previously unknown to be mutated in stomach cancer."  
"Gastric cancer is one of the top causes of cancer death worldwide, and is particularly prevalent in East Asia," Teh adds. "We wanted to contribute to the understanding of a major public health burden that is relatively neglected in Europe and America."  
Given the late detection of tumors and a lack of information on what leads to stomach cancer, treatment is often unsuccessful. In the United States, less than a quarter of patients survive more than five years after diagnosis, even with treatment, and stomach cancer leads to more than 700,000 deaths worldwide each year.  
For the study, the team analyzed tumor tissue and normal tissue from stomach cancer patients using state-of-the-art DNA sequencing technology. The team included researchers and clinicians from three research groups affiliated with Duke-NUS, including one headed by Teh.
"This technology allows us to read the DNA sequence of the genes in each cancer genome for less than $2,000, an incredibly low price," Assoc. Prof. Steven G. Rozen, head of the Computational Systems Biology and Human Genetics Laboratory in Duke-NUS and senior co-author, said in a press release.
Two of the genes identified, FAT4 and ARID1A, earned additional scrutiny, as a further analysis of roughly 100 tumors found that the two genes were mutated in 5 percent and 8 percent of stomach cancers, respectively, and in some patients, portions of the chromosome containing the genes were missing entirely. Manipulation of the genes was found to alter the growth of stomach cancer cells, and as many as 100,000 new cases of stomach cancer could be caused each year by their mutations, making them attractive therapeutic targets.  
"FAT4 is widely expressed, but little is known about the details of its biochemical functions," says Dr. Patrick Tan, associate professor of the Cancer and Stem Cell Biology Program at Duke-NUS and senior author of the study. "It has not previously been a focus of study in human cancers, but a retrospective analysis suggests that FAT4 mutations might also play roles in some other cancers. ARID1A is involved in gene regulation through epigenetics and chromatin remodeling. There was some prior evidence for a role for ARID1A in other cancers, and while our paper was in review another group also found ARID1A to harbor an excess of mutations in gastric cancers."  
Tan says the next step will be to learn more about the roles the genes play, in addition to investigating other genes that were implicated in stomach cancer in the study.  
Duke-NUS' and the NCCS' work on this initiative is the latest in a longstanding relationship between the two organizations since Duke-NUS was founded in 2005 as a strategic collaboration between Duke University School of Medicine and the National University of Singapore. Rozen notes that Tan and Teh have appointments at both organizations.  
"The massively parallel sequencing was carried out at both Duke-NUS and NCCS," he says. "Much of the bioinformatics analysis was done by the Duke-NUS Centre for Computational Biology."  
Duke-NUS and NCCS were joined by collaborators from a variety of other organizations, including the Cancer Science Institute of Singapore, Northwestern University, National University of Singapore, Van Andel Research Institute, Genome Institute of Singapore, Yonsei Cancer Center, Queen's University, Singapore General Hospital and Wellcome Trust Sanger Institute.
The study was supported by the National Medical Research Council of Singapore's Ministry of Health, as part of the Singapore Gastric Cancer Consortium. The study also received funding from Duke-NUS, the Cancer Science Institute of Singapore, Genome Institute of Singapore (Agency for Science, Technology and Research) and the Lee Foundation.

Duke study sheds light on cancer drug resistance  
DURHAM, N.C.—In March, a multinational research team led by scientists at Duke-NUS Graduate Medical School identified a reason why some patients fail to respond to some of the most successful cancer drugs.  
The study was published online in Nature Medicine on March 18.  
Tyrosine kinase inhibitor drugs (TKIs) work effectively in most patients to fight certain blood-cell cancers, such as chronic myelogenous leukemia (CML) and non-small-cell lung cancers (NSCLC) with mutations in the EGFR gene. These precisely targeted drugs shut down molecular pathways that keep these cancers flourishing and include TKIs for treating CML, and the form of NSCLC with EGFR genetic mutations.  
Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore (GIS), Singapore General Hospital and the National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.  
The researchers found that drug resistance occurred because of impaired production of BH3-containing forms of the BIM protein. They confirmed that restoring BIM gene function with the BH3 drugs worked to overcome TKI resistance in both types of cancer.  
"BH3-mimetic drugs are already being studied in clinical trials in combination with chemotherapy, and we are hopeful that BH3 drugs in combination with TKIs can actually overcome this form of TKI resistance in patients with CML and EGFR non-small-cell lung cancer," said S. Tiong Ong, the senior author of the study and associate professor in the Cancer and Stem Cell Biology Signature Research Programme at Duke-NUS. "We are working closely with GIS and the commercialization arm of the Agency for Science, Technology & Research (A*STAR), to develop a clinical test for the BIM gene variant, so that we can take our discovery quickly to the patient."  
According to the researchers, if a drug combination does override TKI resistance in people, this will be good news for those with the BIM gene variant, which occurs in about 15 percent of the typical East Asian population. By contrast, no people of European or African ancestry were found to have this gene variant.
"While it's interesting to learn about this ethnic difference for the mutation, the greater significance of the finding is that the same principle may apply for other populations," said Dr. Patrick Casey, senior vice dean for research at Duke-NUS. "There may well be other, yet to be discovered gene variations that account for drug resistance in different world populations. These findings underscore the importance of learning all we can about cancer pathways, mutations, and treatments that work for different types of individuals. This is how we can personalize cancer treatment and ultimately control cancer."
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