Singapore Researchers Identify 600 New Mutated Genes in Stomach Cancer
By Allison Proffitt
April 10, 2012 | SINGAPORE—Researchers in Singapore have identified over 600 previously unknown genes mutated in stomach cancer. Their findings were published online in Nature Genetics on April 8.
The high number of mutated genes proves the heterogeneity of gastric cancers, said Patrick Tan, senior author of the study and associate professor in the Cancer and Stem Cell Biology Program at the Duke-NUS Graduate Medical School.
“We sequenced the exomes of a number of gastric cancers and what we found was there were many, many genes that were mutated in gastric cancers but the frequency of the mutations wasn’t very high. We found genes that were only mutated in 5% or 10% of cases,” Tan told Bio-IT World. Only one gene that codes for p53—what Tan called the “holy grail of the whole cancer field”—was found to be mutated in more than 50% of the cancers tested.
But even these small percentages don’t mean small patient populations. 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 is often unsuccessful because of late detection of tumors and a poor understanding of the causes.
“These individual percentages may seem low, but in the context of the worldwide [disease] incidence 5%-10% is actually quite substantial—it could be 40,000 to 80,000 people,” Tan said.
Three research groups participated in the study led by Tan, who also leads the Genomic Oncology Program at the Cancer Sciences Institute of Singapore and is a group leader at the Genome Institute of Singapore; Steven G. Rozen, who heads the Computational Systems Biology and Human Genetics Laboratory; and Teh Bin Tean, director of the NCCS-VARI Translational Research Laboratory at the National Cancer Center Singapore.
Pathway Focus
Though the disease-causing mutations seem spread over a large number of genes, they tend to disrupt a few key pathways.
Tan, Rozen, Teh and their colleagues started by doing “very deep sequencing” on the exomes of 15 gastric tumor samples and normal tissues from the same patients. After their initial screening, the researchers focused on two genes and added tumor and normal pairs from an additional 100 patients.
Tumor samples were all chosen from Singaporean patients and supplied by the National Cancer Centre of Singapore and the tissue bank at Singapore General Hospital. Sequencing was done on Illumina HiSeq and GAII instruments by National Cancer Centre of Singapore, Duke-NUS, and the Genome Institute of Singapore.
“We found two genes that we focused on: ARID1A—involved in the modification of chromatin; and FAT4—involved in cell adhesion,” Tan explained. “We chose these two genes because they’re representative of two major affected pathways [disrupted by the mutated] genes. Even though each individual gene was mutated in only small fraction of tumors, many of these genes fell into similar pathways, with the same end result.”
The findings reinforce the importance of personalized treatments, Tan said. “Our treatments need to move away from treating all gastric cancers the same toward more personalized approaches to treating individual patients.”
He hopes that the work sequencing mutated genes as well as identifying their common disrupted pathways will shed more light on treating such varied cancers. In the next year, Tan’s group plans to focus on the “underlying molecular genetics of the ‘Asian’ cancers,” specifically liver, lung and other cancers with high incidence in Asian populations.
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; Northwestern University, Chicago; Yonsei Cancer Center, Seoul, South Korea; Queen's University, Belfast, UK; and Wellcome Trust Sanger Institute, Hinxton, UK.