Scientists at the National Cancer Centre Singapore (NCCS) have discovered a new link between a chromosomal fragile site, FRA18C, and gastric cancer. This research may provide new insights for predicting survival and more effective treatment of gastric cancers. Fragile sites are specific parts of various chromosomes that tend to break when cells are exposed to stress. Although some chromosomal fragile sites were known to be associated with different cancers, FRA18C was not known to be linked to any cancer.

Professor Kon Oi Lian and co–authors published a research study detailing a breakpoint in chromosome 18 which they found in several gastric cancer cell lines and also in 22% of gastric cancers in Singapore General Hospital. The breakpoint was located in FRA18C and reduced production of a protein known as DOK6. Patients whose gastric cancers had low amounts of DOK6 protein survived significantly longer (2100 days) than those whose cancers had high DOK6 (533 days). Little is known about the function of DOK6, an adaptor protein. Before this study, it was only known to be involved in normal brain development. This discovery is the first that links DOK6 to cancer and the first to implicate DOK6 as a potential prognostic biomarker for gastric cancer.

The NCCS team found that several cancer–causing signalling pathways known to be active in gastric cancers were strikingly diminished in gastric cancers with low DOK6 protein. This provided a plausible explanation for the longer survival of patients with low DOK6 gastric cancers. The finding that multiple molecular pathways concurrently sustain the progression of gastric cancers suggests that such cancers could be more effectively treated with combinations of anti–cancer drugs which simultaneously block all activated pathways.

Currently, gastric cancers may be treated with drugs designed to block specific pathways considered important in tumour growth. Molecularly targeted therapy is commonly directed at single pathways. However, this approach may soon be a thing of the past. “People are now beginning to understand that what keeps cancer cells surviving and growing is that they’re not simply making use of one cancer pathway. Cancer cells survive because they depend on and make use of different pathways concurrently,” explained Prof Kon.

This would mean the approach should be changed from “one drug, one target” to a better approach of “one drug, many targets” or “many drugs, many targets” in order to block multiple cancer growth pathways and improve survival.

This study also involved researchers from Singapore General Hospital, National Neuroscience Institute, Singapore and Wellcome Trust Sanger Institute, UK. It was supported by the NCC Research Fund from the National Cancer Centre Singapore, and a grant from the National Medical Research Council. Prof Kon is Principal Investigator Mentor in NCCS.

This study was the outcome of 5 years of research, and was recently published in the journal Precision Oncology.