An international team of scientists, led by researchers from the Duke-NUS Graduate Medical School (Duke-NUS) in Singapore and National Cancer Centre of Singapore, has identified hundreds of novel genes that are mutated in stomach cancer, the second-most lethal cancer worldwide.
The study, which appears online on April 8, 2012 in Nature Genetics, paves the way for treatments tailored to the genetic make-up of individual stomach tumors.
Stomach cancer is the second leading cause of cancer death globally with more than 700,000 deaths each year, and is particularly common in East Asia. Treatment of this deadly disease is often difficult and unsuccessful because of late detection of tumors and a poor understanding of the causes. In the United States, less than a quarter of patients survive more than five years after diagnosis, even after treatment.
“Until now, the genetic abnormalities that cause stomach cancers are still largely unknown, which partially explain the overall poor treatment outcome,” said Patrick Tan, M.D., Ph.D., senior author of the study and associate professor in the Cancer and Stem Cell Biology Program at Duke-NUS. Tan also leads the Genomic Oncology Program at the Cancer Sciences Institute of Singapore and is a group leader at the Genome Institute of Singapore.
Using state-of-the-art DNA sequencing technology, the research team analyzed tumor and normal tissue from stomach cancer patients, which led to the discovery of the novel gene mutations.
“This technology allows us to read the DNA sequence of the genes in each cancer genome,” said co-senior author Steven G. Rozen, Ph.D., who heads the Computational Systems Biology and Human Genetics Laboratory in Duke-NUS. “This is also a major team effort involving both basic scientists and clinicians.”
The team included scientists and clinicians from three research groups affiliated with Duke-NUS, including one headed by co-senior author Teh Bin Tean, M.D., Ph.D., director of the NCCS-VARI Translational Research Laboratory at the National Cancer Center Singapore.
HEREDITARY DIFFUSE GASTRIC CANCER (HDGC)
Stomach (gastric) cancer is the fourth most common cause of cancer worldwide, and the second leading cause of cancer deaths worldwide. The American Cancer Society has estimated that 21,000 new cases of gastric cancer will be diagnosed in the United States in 2010, and that more than 10,000 Americans would die of gastric cancer during the year. Because gastric cancer is difficult to diagnose, it is often diagnosed at a late stage with a poor prognosis. The treatment for gastric cancer is surgery and chemotherapy. The overall 5-year survival rate is 24.3%.
An estimated 1-3% of cases of gastric cancer are caused by Hereditary Diffuse Gastric Cancer. Hereditary diffuse gastric cancer (HDGC) is an inherited cancer syndrome that leads to an increased risk for both diffuse gastric cancer and lobular breast cancer. Patients who inherit the genetic mutation for HDGC are at high risk for developing gastric cancer at a young age.
“Our study is one of the first gastric cancer studies to investigate the vast majority of human genes at the single nucleotide level,” Teh said. “We screened 18,000 human genes and identified over 600 genes that were previously unknown to be mutated in stomach cancer.”
Two of the 600 genes identified that were associated with stomach cancer, FAT4 and ARID1A proved to be particularly interesting. A further analysis of about 100 stomach tumors found these genes to be mutated in 5 percent and 8 percent of stomach cancers, respectively. In some patients, portions of the chromosome containing the two genes were found to be missing, providing further evidence that genetic defects affecting these genes occur frequently in stomach cancer.
Benign Gastric Polyps
Benign gastric polyps are found incidentally in 2-3% of upper gastrointestinal endoscopies. Their incidence increases with patient age. Small polyps are almost always asymptomatic. Larger polyps may bleed due to erosions or ulceration. Very large distal polyps may produce obstructive symptoms.
Small hyperplastic and fundic gland polyps are relatively common. They are generally regarded as being of no significance although multiple fundic gland polyps with evidence of dysplasia can occur in familial adenomatous polyposis (FAP). Fundic gland polyps and, to a lesser extent, hyperplastic polyps, occur with increased frequency in patients on long-term proton pump inhibitor therapy.
Inflammatory fibroid polyps (IFPs) are uncommon solitary lesions that arise in the distal stomach. They usually originate submucosally however the overlying mucosa commonly develops erosions or ulceration. IFPs are felt to be reactive in nature and are composed of a mixture of proliferating fibroblasts, blood vessels and inflammatory cells.
Eosinophils are often present. Helicobacter pylori has been implicated in the etiology of IFPs as have chemical and mechanical irritants.
Adenomatous polyps in the stomach usually arise against a background of chronic atrophic gastritis with intestinal metaplasia although they too can occur in FAP. Gastric adenomata are composed of dysplastic epithelium with tubular and/or villous architecture. Polyp size and the grade of dysplasia are felt to be predictors of progression to carcinoma. Because gastric adenomata, like those in the colon, represent a pre-malignant condition, excision (usually possible endoscopically) is the treatment of choice.
Lab experiments demonstrated the importance of these two genes in driving stomach cancer, as manipulation of FAT4 and ARID1A function altered the growth of stomach cancer cells.
“More research is required to realize the clinical implications of these findings. ARID1A and FAT4 are likely also involved in many other cancer types, not just stomach cancer,” noted Tan, whose research team is actively working on translating the results of this study into clinical applications.
With more than 100,000 new cases worldwide of stomach cancer each year likely to be caused by mutations in FAT4 or ARID1A, drugs against these targets may someday lead to more effective treatment of stomach tumors and other cancers.
Researchers from the British Columbia Cancer Agency in Vancouver, Canada studied almost 40 families in which at least one member had been diagnosed with hereditary diffuse gastric cancer, to determine the rate at which changes occurred in a specific gene called CDH1. In addition, they determined whether the mutations had arisen independently in the affected person or were present in different generations of each family.
Over a dozen mutations in the target gene were identified, six of which had not been identified before. One of the newly identified mutations found in four of the families was associated with other genes in a way suggesting that it was likely passed on from generation to generation. The analysis suggested that the mutation originally appeared in one person and gradually accumulated in the geographically isolated population over time. The fact that all four families originated from the same region of Newfoundland fits this suggestion. The centuries-long isolation of people living in Newfoundland has also lead to the accumulation of some other genetic mutations, which are now considered specific to this population.
Since the defective gene can be detected in blood, screening of people for the mutation is possible. While this is relavent everywhere, for now researchers recommend that people in Newfoundland be screened for diffuse gastric cancer.
In addition to Duke-NUS and the National Cancer Center Singapore, the study also involved collaborators from the Cancer Sciences Institute of Singapore; Genome Institute of Singapore; National University of Singapore; Singapore General Hospital; Van Andel Research Institute, Michigan, USA; Northwestern University, Chicago, USA; Yonsei Cancer Center, Seoul, South Korea; Queen’s University, Belfast, UK; and Wellcome Trust Sanger Institute, Hinxton, UK.
Support for this study was provided by the National Medical Research Council, as part of the Singapore Gastric Cancer Consortium. Funding was also received from the Cancer Sciences Institute of Singapore, Duke-NUS Graduate Medical School, Genome Institute of Singapore (Agency for Science, Technology and Research), and the Lee Foundation.
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.
Mary Jane Gore
Duke University Medical Center