Ong Chee Wee
Email Address
csiocw@nus.edu.sg
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Publication Dual-colour HER2/Chromosome 17 chromogenic in situ hybridisation assay enables accurate assessment of HER2 genomic status in gastric cancer and has potential utility in HER2 testing of biopsy samples(2011-10) Yan, B.; Yau, E.X.; Choo, S.N.; Ong, C.W.; Yong, K.J.; Pang, B.; Salto-Tellez, M.; CANCER SCIENCE INSTITUTE OF SINGAPORE; PATHOLOGYBackground: Determination of HER2 protein expression by immunohistochemistry (IHC) and genomic status by fluorescent in situ hybridisation (FISH) are important in identifying a subset of high HER2-expressing gastric cancers that might respond to trastuzumab. Although FISH is considered the standard for determination of HER2 genomic status, brightfield ISH is being increasingly recognised as a viable alternative. Also, the impact of HER2 protein expression/genomic heterogeneity on the accuracy of HER2 testing has not been well studied in the context of gastric biopsy samples. Aims/methods: To study the utility of brightfield ISH in the evaluation of HER2 genomic status, the correlation coefficient between dual-colour HER2/Chromosome 17 chromogenic in situ hybridisation (CISH) and FISH was ascertained. To study the impact of intratumoral heterogeneity on the accuracy of HER2 testing, the concordance rate of HER2 protein expression/genomic status between matched biopsies and surgical resection specimens of high HER2-expressing gastric cancers was ascertained. Results: The dual-colour CISH assay showed a 100% concordance rate with FISH results in 119 samples (Pearson correlation coefficient 0.987, pPublication Clinical and therapeutic relevance of PIM1 kinase in gastric cancer(2012-04) Yan, B.; Yau, E.X.; Samanta, S.; Ong, C.W.; Yong, K.J.; Ng, L.K.; Bhattacharya, B.; Lim, K.H.; Soong, R.; Yeoh, K.G.; Deng, N.; Tan, P.; Lam, Y.; Salto-Tellez, M.; DUKE-NUS GRADUATE MEDICAL SCHOOL S'PORE; CANCER SCIENCE INSTITUTE OF SINGAPORE; CHEMISTRYBackground Gastric cancer is a leading cause of cancerrelated mortality, and chemotherapeutic options are currently limited. PIM1 kinase, an oncogene that promotes tumorigenesis in several cancer types, might represent a novel therapeutic target in gastric cancer. Methods We studied the expression and genomic status of PIM1 in human primary gastric normal and tumor tissue samples by immunohistochemistry and array-based comparative genomic hybridization (aCGH). To ascertain whether PIM1 expression predicted susceptibility to PIM1 kinase-specific inhibition, the cytotoxic effect of a previously reported PIM1-specific small molecular inhibitor (K00135) was investigated in two gastric cancer cell lines with high (IM95) and undetectable (NUGC-4) PIM1 expression levels. Results PIM1 expression was exclusively nuclear in normal gastric epithelial cells, while aberrant expression/localization (decreased nuclear and/or increased cytoplasmic expression) was observed in 75.6% (68/90) of the human gastric cancer tissue samples, with a significant inverse correlation between nuclear and cytoplasmic expression levels. Clinicopathological analyses revealed that decreased nuclear PIM1 expression correlated with poorer survival and greater depth of tumor invasion, while increased cytoplasmic PIM1 expression correlated inversely with the presence of lymphovascular invasion. Highlevel PIM1 amplification was identified in 10.5% of gastric cancers by aCGH. K00135 impaired the survival of IM95, while it had no significant effect on NUGC-4 survival. Conclusion Our findings demonstrate the clinical and therapeutic relevance of PIM1 in gastric cancers, and suggest that PIM1 represents a potential therapeutic target. © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2011.Publication A study of HER2 gene amplification and protein expression in gastric cancer(2010-09) Yan, B.; Yau, E.X.; Omar, S.S.B.; Ong, C.W.; Pang, B.; Yeoh, K.G.; Salto-Tellez, M.; CANCER SCIENCE INSTITUTE OF SINGAPORE; PATHOLOGYBackground: Gastric cancer is a leading cause of cancer-related mortality, and current treatment outcomes for advanced disease remain poor. HER2 has been identified as a potential candidate for targeted therapy in gastric cancers displaying HER2 gene amplification and protein overexpression. Aims: To study the prevalence rate of HER2 gene amplification/overexpression in a local population, and determine the concordance rate between the various modalities. Methods: 128 gastric cancer samples were analysed by fluorescence (FISH) and chromogenic (CISH) in situ hybridisation and immunohistochemistry (IHC). The relation between HER2 status and various clinicopathological parameters was also analysed. Results: 11.7% (15/128) and 9.4% (12/128) of gastric cancers displayed HER2 gene amplification and protein overexpression (score 3+), respectively, with a perfect correlation between the FISH and CISH analyses. There was also a significant inverse correlation between overall survival and HER2 protein overexpression in intestinal-type gastric carcinomas (pPublication Proteomic analysis of colorectal cancer metastasis: Stathmin-1 revealed as a player in cancer cell migration and prognostic marker(2012-02-03) Tan, H.T.; Wu, W.; Ng, Y.Z.; Zhang, X.; Yan, B.; Ong, C.W.; Tan, S.; Salto-Tellez, M.; Hooi, S.C.; Chung, M.C.M.; CANCER SCIENCE INSTITUTE OF SINGAPORE; BIOLOGICAL SCIENCES; BIOCHEMISTRYMetastasis accounts largely for the high mortality rate of colorectal cancer (CRC) patients. In this study, we performed comparative proteome analysis of primary CRC cell lines HCT-116 and its metastatic derivative E1 using 2-D DIGE. We identified 74 differentially expressed proteins, many of which function in transcription, translation, angiogenesis signal transduction, or cytoskeletal remodeling pathways, which are indispensable cellular processes involved in the metastatic cascade. Among these proteins, stathmin-1 (STMN1) was found to be highly up-regulated in E1 as compared to HCT-116 and was thus selected for further functional studies. Our results showed that perturbations in STMN1 levels resulted in significant changes in cell migration, invasion, adhesion, and colony formation. We further showed that the differential expression of STMN1 correlated with the cells' metastatic potential in other paradigms of CRC models. Using immunohistochemistry, we also showed that STMN1 was highly expressed in colorectal primary tumors and metastatic tissues as compared to the adjacent normal colorectal tissues. Furthermore, we also showed via tissue microarray analyses of 324 CRC tissues and Kaplan-Meier survival plot that CRC patients with higher expression of STMN1 have poorer prognosis. © 2011 American Chemical Society.Publication TRARESA: A tissue microarray-based hospital system for biomarker validation and discovery(2008) Das, K.; Peh, B.K.; Putti, T.C.; Teh, M.; Soong, R.; Salto-Tellez, M.; Mohd, Omar M.F.; Shah, N.; Ong, C.W.; Bin, Abdul Rashid S.; Chia, K.S.; Tan, P.H.; CENTRE FOR MOLECULAR EPIDEMIOLOGY; NATIONAL UNIVERSITY MEDICAL INSTITUTES; PATHOLOGY; COMMUNITY,OCCUPATIONAL & FAMILY MEDICINEPublication Oncofetal gene SALL4 in aggressive hepatocellular carcinoma(2013) Yong, K.J.; Gao, C.; Lim, J.S.J.; Yan, B.; Yang, H.; Dimitrov, T.; Kawasaki, A.; Ong, C.W.; Wong, K.-F.; Lee, S.; Ravikumar, S.; Srivastava, S.; Tian, X.; Poon, R.T.; Fan, S.T.; Luk, J.M.; Dan, Y.Y.; Salto-Tellez, M.; Chai, L.; Tenen, D.G.; CANCER SCIENCE INSTITUTE OF SINGAPOREBACKGROUND: Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment. METHODS: We screened specimens obtained from patients with primary hepatocellular carcinoma for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we used in vitro functional and in vivo xenograft assays. RESULTS: SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have hepatocellular carcinoma and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4 -positive hepatocellular carcinomas. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (the phosphatase and tensin homologue protein) and inhibited tumor formation in xenograft models in vivo. CONCLUSIONS: SALL4 is a marker for a progenitor subclass of hepatocellular carcinoma with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma. Copyright © 2013 Massachusetts Medical Society.Publication Sequential expression of putative stem cell markers in gastric carcinogenesis(2011-08-23) Wang, T.; Ong, C.W.; Shi, J.; Srivastava, S.; Yan, B.; Cheng, C.L.; Yong, W.P.; Chan, S.L.; Yeoh, K.G.; Iacopetta, B.; Salto-Tellez, M.; CANCER SCIENCE INSTITUTE OF SINGAPORE; PATHOLOGYBackground: Gastric carcinogenesis has been well documented in the step-wise histopathological model, known as Correa pathway. Several biomarkers including CD44, Musashi-1 and CD133 have been reported as putative stem cell (PSC) markers. Methods: We investigated expression of PSC markers CD44, Musashi-1 and CD133 in relation to gastric carcinogenesis and prognosis and chemoresponse. Immunohistochemistry staining was performed in gastric cancer (GC) clinical specimens representing different steps of the Correa pathway. Gastric cancer samples taken before and after neoadjuvant chemotherapy with docetaxel, cisplatin and capecitabine (DCX) were also evaluated for PSC marker expression. Results: We showed that the expression of three PSC markers was significantly elevated in GC relative to normal gastric mucosa (P0.001 for each marker). Precancerous lesions, including intestinal metaplasia and dysplasia, demonstrated increased expression of CD44 and Musashi-1. CD133 was predominantly expressed along the border between intramucosal carcinoma and connective tissue at later stages. High CD44 and CD133 expression showed prognostic value for worse patient survival (P0.014 and P0.019, respectively). A small number of tumours with high expression of CD44 and CD133 showed pathological response to DCX-based neoadjuvant chemotherapy. Conclusion: CD44 and Musashi-1 are frequently expressed in both premalignant gastric lesions and invasive GC, whereas CD133 expression is restricted mainly to neoplastic tissues. © 2011 Cancer Research UK All Rights Reserved.Publication RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α(2012-01-26) Huang, B.; Qu, Z.; Ong, C.W.; Tsang, Y.-H.N.; Xiao, G.; Shapiro, D.; Salto-Tellez, M.; Ito, K.; Ito, Y.; Chen, L.-F.; CANCER SCIENCE INSTITUTE OF SINGAPORETranscription factor RUNX3 is inactivated in a number of malignancies, including breast cancer, and is suggested to function as a tumor suppressor. How RUNX3 functions as a tumor suppressor in breast cancer remains undefined. Here, we show that about 20% of female Runx3 / mice spontaneously developed ductal carcinoma at an average age of 14.5 months. Additionally, RUNX3 inhibits the estrogen-dependent proliferation and transformation potential of ERα-positive MCF-7 breast cancer cells in liquid culture and in soft agar and suppresses the tumorigenicity of MCF-7 cells in severe combined immunodeficiency mice. Furthermore, RUNX3 inhibits ERα-dependent transactivation by reducing the stability of ERα. Consistent with its ability to regulate the levels of ERα, expression of RUNX3 inversely correlates with the expression of ERα in breast cancer cell lines, human breast cancer tissues and Runx3 / mouse mammary tumors. By destabilizing ERα, RUNX3 acts as a novel tumor suppressor in breast cancer. © 2012 Macmillan Publishers Limited All rights reserved.Publication CD133 expression predicts for non-response to chemotherapy in colorectal cancer(2010) Ong, C.W.; Kim, L.G.; Soong, R.; Salto-Tellez, M.; Kong, H.H.; Low, L.Y.; Iacopetta, B.; CANCER SCIENCE INSTITUTE OF SINGAPORE; PATHOLOGYPublication KRAS mutation analysis in a complex molecular diagnostic referral practice: The need for test redundancy(2012-12) Pang, B.; Ong, C.-W.; Chong, M.-L.; Muliana-Ismail, T.; Soong, R.; Salto-Tellez, M.; CANCER SCIENCE INSTITUTE OF SINGAPORE
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