Singapore Gastric Cancer Consortium

I) Gastric Cancer Epidemiology Programme (GCEP) Cohort study

Only by screening is it possible to detect early gastric cancers. Our GCEP study is the first ever systemic study of screening for gastric cancer in a cohort of 3000 subjects. Benefits to patients include being diagnosed and treated for early gastric cancer, and in treatment of risk factors to reduce their risk of developing gastric cancer. This study provides information on the yield of screening and true risk of pre-cancerous lesions like intestinal metaplasia and atrophic gastritis which will help us design a cost-effective algorithm for targeted screening of gastric cancer in high-risk groups in the Singapore population (Leung et al, Lancet Oncology 2008).

II) New Methods for Early Detection of Gastric Cancer: Development of a novel Raman-near-infra-red autofluorescence endoscopic imaging system to improve early detection of gastric cancer and precancer

We have developed the first in vivo Raman endoscopic system that is being used live in endoscopies on human patients (Huang et al, Optics Letters 2009). The utility of this novel technique for improving early detection of gastric cancer is now being tested in clinical trials.

So far, we have correlated the origins of biochemical and biomolecular structures of Raman spectra with neoplastic and pre-neoplastic transformation in the gastric mucosa. There are specific spectral differences in Raman spectra between normal and dysplasia tissue (Teh et al, British Journal of Cancer 2008). We have also developed a number of effective diagnostic algorithms for rapid gastric cancer (Teh et al, J Biomed Optics 2008) and pre-cancer detection (Teh et al, J Raman Spectroscopy 2009).

III) New Methods for Early Detection of Gastric Cancer: Evaluation of the use of confocal endomicroscopy (CE) in conjunction with chromoendoscopy in the detection of gastric pre-neoplasia and neoplasia

CE is an advanced optical imaging technique which uses high magnification to detect cellular changes in the stomach lining, with the potential of making a diagnosis of cancer on the spot without waiting several days for laboratory results. We have (i) established confocal diagnostic features for normal and pathologic gastric mucosa; (ii) initiated randomized-controlled trial on confocal diagnosis of gastric neoplasia and; (iii) initiated pilot study in establishing confocal features for chronic gastritis.

I) RUNX3 is a Critical Tumour Suppressor in Gastric Cancer

Our group has shown that RUNX3 is a critical tumour suppressor gene in gastric cancer in both animal models and in human gastric cancer.

We showed wild-type RUNX3 attenuates Wnt signalling by interacting with a transcription factor, TCF4 (Ito et al, Cancer Cell 2008) while a RUNX3 mutation, R122C, found in human gastric cancer (Ito et al, Cell 2002) does not. Since TCF4 together with β-catenin is a nuclear effector of Wnt signalling pathway, the results strongly suggest that Wnt signalling pathway functions as an oncogenic pathway in gastric cancer (Ito K et al, manuscript in preparation).

We reported earlier that Runx3+/+ cells isolated from stomach epithelium display polarity and form a cell sheet when cultivated in collagen gel, whereas similarly isolated Runx3-/- cells do not show any polarity, do not form cell sheet and grow randomly under the same culture conditions (Fukamachi et al, Cancer Sci 2008). This suggested that some cell surface molecules involved in cell-cell junction might be a target of RUNX3. We found that one of the tight junction proteins, Claudin-1, is a direct positive target of Runx3 and Claudin-1 has tumour suppressive function. This is interesting because Claudin-1 is a negative target of Snail and Slug that induces epithelial mesenchymal transition (EMT). These results suggest that part of the tumour suppressor function of RUNX3 may be affected by an inhibition of EMT. (Chang et al, Gastroenterology 2009).

I) Genetic Pathways Predict Clinical Prognosis in Gastric Cancer

With current treatments, less than a quarter of gastric cancer (GC) patients survive longer than five years after surgery, making GC the second highest cause of global cancer mortality. Individual GCs are highly disparate in their cellular characteristics and responses to standard chemotherapeutic drugs. Pathway based approaches, rather than single gene studies, may help to unravel this complexity. We have applied computational approaches to identify connections between molecular pathways and cancer profiles. In a large scale study of more than 300 patients, we identified subgroups of gastric cancers distinguishable by their patterns of driving molecular pathways. We showed that these identified subgroups are clinically relevant in predicting survival duration and may prove useful in guiding the choice of targeted therapies designed to interfere with these molecular pathways. We also identified specific gastric cancer cell lines mirroring these pathway subgroups, which should facilitate the pre-clinical assessment of responses to targeted therapies in each subgroup (Chia et al, PLoS Genetics 2009).

II) Early Phase Clinical Trials: Neoadjuvant Therapies in Operable Gastric Cancer

In patients with early gastric cancer, we have evaluated the role of neoadjuvant chemotherapy of docetaxel, cisplatin and capecitabine before surgery. Preliminary analysis of pre-treatment tumour tissues suggested that a high DNA methylation score correlated with improved treatment outcome and may be used to select patients that may benefit from neoadjuvant chemotherapy. The study is still on-going, and will be used to validate in-vitro derived genomic signature of drug response.

III) Working Prototype of Robot Endoscope

Investigators in the SGCC have developed a working prototype of a robot endoscope, called "MASTER" (Master And Slave Transluminal Endoscopic Robot) (Phee et al, Intelligent Medical Technologies and Biomedical Engineering 2009). This allows endoscopic operations within the lumen of the digestive tract with a greatly increased number of freedoms of movements compared to conventional endoscopes. This will have tremendous clinical applications in making possible internal luminal operations such as removal of stomach cancers and in successfully stopping internal bleeding in difficult cases. Clinical applications using this robot have been described (Ho et al, Gastrointestinal Endoscopy 2009; and Phee et al, Gastrointestinal Endoscopy 2009).