Researchers have the stomach for cancer

SINGAPORE—Hundreds of novel genes that are mutated instomach cancer have recently been identified, providing a much-needed update onthe second most lethal cancer in the world. The research, done by aninternational team of researchers led by members from Duke-NUS Graduate MedicalSchool (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 toinvestigate the vast majority of human genes at the single nucleotide level,"Prof. Teh Bin Tean, director of the NCCS-VARI Translational Research Laboratoryat NCCS and senior co-author of the study, said in a press release. "Wescreened 18,000 human genes and identified over 600 genes that were previouslyunknown to be mutated in stomach cancer."

"Gastric cancer is one of the top causes of cancer deathworldwide, and is particularly prevalent in East Asia," Teh adds. "We wanted tocontribute to the understanding of a major public health burden that isrelatively neglected in Europe and America."

Given the late detection of tumors and a lack of informationon what leads to stomach cancer, treatment is often unsuccessful. In the UnitedStates, less than a quarter of patients survive more than five years afterdiagnosis, even with treatment, and stomach cancer leads to more than 700,000deaths worldwide each year.

For the study, the team analyzed tumor tissue and normaltissue from stomach cancer patients using state-of-the-art DNA sequencingtechnology. The team included researchers and clinicians from three researchgroups affiliated with Duke-NUS, including one headed by Teh.

"This technology allows us to read the DNA sequence of thegenes in each cancer genome for less than $2,000, an incredibly low price,"Assoc. Prof. Steven G. Rozen, head of the Computational Systems Biology andHuman Genetics Laboratory in Duke-NUS and senior co-author, said in a pressrelease.

Two of the genes identified, FAT4 and ARID1A, earnedadditional scrutiny, as a further analysis of roughly 100 tumors found that thetwo genes were mutated in 5 percent and 8 percent of stomach cancers, respectively,and in some patients, portions of the chromosome containing the genes weremissing entirely. Manipulation of the genes was found to alter the growth ofstomach cancer cells, and as many as 100,000 new cases of stomach cancer couldbe caused each year by their mutations, making them attractive therapeutictargets.

"FAT4 is widely expressed, but little is known about thedetails of its biochemical functions," says Dr. Patrick Tan, associateprofessor of the Cancer and Stem Cell Biology Program at Duke-NUS and seniorauthor of the study. "It has not previously been a focus of study in humancancers, but a retrospective analysis suggests that FAT4 mutations might alsoplay roles in some other cancers. ARID1A is involved in gene regulation throughepigenetics and chromatin remodeling. There was some prior evidence for a rolefor ARID1A in other cancers, and while our paper was in review another groupalso found ARID1A to harbor an excess of mutations in gastric cancers."

Tan says the next step will be to learn more about the rolesthe genes play, in addition to investigating other genes that were implicatedin stomach cancer in the study.

Duke-NUS' and the NCCS' work on this initiative is thelatest in a longstanding relationship between the two organizations sinceDuke-NUS was founded in 2005 as a strategic collaboration between DukeUniversity School of Medicine and the National University of Singapore. Rozennotes that Tan and Teh have appointments at both organizations.

"The massively parallel sequencing was carried out at bothDuke-NUS and NCCS," he says. "Much of the bioinformatics analysis was done bythe Duke-NUS Centre for Computational Biology."

Duke-NUS and NCCS were joined by collaborators from avariety of other organizations, including the Cancer Science Institute ofSingapore, Northwestern University, National University of Singapore, Van AndelResearch 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 ofSingapore's Ministry of Health, as part of the Singapore Gastric CancerConsortium. The study also received funding from Duke-NUS, the Cancer ScienceInstitute 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 byscientists at Duke-NUS Graduate Medical School identified a reason why somepatients 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 inmost patients to fight certain blood-cell cancers, such as chronic myelogenousleukemia (CML) and non-small-cell lung cancers (NSCLC) with mutations in theEGFR gene. These precisely targeted drugs shut down molecular pathways thatkeep these cancers flourishing and include TKIs for treating CML, and the formof NSCLC with EGFR genetic mutations.

Now the team at Duke-NUS Graduate Medical School inSingapore, working with the Genome Institute of Singapore (GIS), SingaporeGeneral Hospital and the National Cancer Centre Singapore, has discovered thatthere is a common variation in the BIM gene in people of East Asian descentthat contributes to some patients' failure to benefit from these tyrosinekinase inhibitor drugs.

The researchers found that drug resistance occurred becauseof impaired production of BH3-containing forms of the BIM protein. Theyconfirmed that restoring BIM gene function with the BH3 drugs worked toovercome TKI resistance in both types of cancer.

"BH3-mimetic drugs are already being studied in clinicaltrials in combination with chemotherapy, and we are hopeful that BH3 drugs incombination with TKIs can actually overcome this form of TKI resistance inpatients with CML and EGFR non-small-cell lung cancer," said S. Tiong Ong, thesenior author of the study and associate professor in the Cancer and Stem CellBiology Signature Research Programme at Duke-NUS. "We are working closely withGIS and the commercialization arm of the Agency for Science, Technology &Research (A*STAR), to develop a clinical test for the BIM gene variant, so thatwe can take our discovery quickly to the patient."

According to the researchers, if a drug combination doesoverride TKI resistance in people, this will be good news for those with theBIM gene variant, which occurs in about 15 percent of the typical East Asianpopulation. By contrast, no people of European or African ancestry were foundto have this gene variant.

"While it's interesting to learn about this ethnic difference for themutation, the greater significance of the finding is that the same principlemay apply for other populations," said Dr. Patrick Casey, senior vice dean forresearch at Duke-NUS. "There may well be other, yet to be discovered genevariations that account for drug resistance in different world populations.These findings underscore the importance of learning all we can about cancerpathways, mutations, and treatments that work for different types ofindividuals. This is how we can personalize cancer treatment and ultimatelycontrol cancer."