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Translational aspects of genetic factors in the prediction of drug response variability: a case study of warfarin pharmacogenomics in a multi-ethnic cohort from Asia

Chan SL, Suo C, Lee SC, Goh BC, Chia KS, Teo YY

Pharmacogenomics J, 2012 Aug;12(4):312-8.
PMID: 21383771 DOI: 10.1038/tpj.2011.7

Genetic markers displaying highly significant statistical associations with complex phenotypes may not necessarily possess sufficient clinical validity to be useful. Understanding the contribution of these markers beyond readily available clinical biomarkers is particularly important in pharmacogenetics. We demonstrate the utility of genetic testing using the example of warfarin in a multi-ethnic setting comprising of three Asian populations that are broadly representative of the genetic diversity for half of the population in the world, especially as distinct interethnic differences in warfarin dose requirements have been previously established. We confirmed the roles of three well-established loci (CYP2C9, VKORC1 and CYP4F2) in explaining warfarin dosage variation in the three Asian populations. In addition, we assessed the relationship between ethnicity and the genotypes of these loci, observing strong correlations at VKORC1 and CYP4F2. Subsequently, we established the additional utility of these genetic factors in predicting warfarin dose beyond ethnicity and clinical biomarkers through performing a series of systematic cross-validation analyses of the relative predictive accuracies of various fixed-dose regimen, clinical and genetic models. Through a pharmacogenetics model for warfarin, we show the importance of genetic testing beyond readily available clinical biomarkers in predicting dose requirements, confirming the role of genetic profiling in personalized medicine.
Fulltext Human Ribosomal Proteins RPeL27, RPeL43, and RPeL41 Are Upregulated in Nasopharyngeal Carcinoma Cell Lines

Sim EU, Chan SL, Ng KL, Lee CW, Narayanan K

Dis Markers, 2016;2016:5179594.
PMID: 28018022 DOI: 10.1155/2016/5179594

Apart from their canonical role in ribosome biogenesis, there is increasing evidence of ribosomal protein genes' involvement in various cancers. A previous study by us revealed significant differential expression of three ribosomal protein genes (RPeL27, RPeL41, and RPeL43) between cell lines derived from tumor and normal nasopharyngeal epithelium. However, the results therein were based on a semiquantitative assay, thus preliminary in nature. Herein, we provide findings of a deeper analysis of these three genes in the context to nasopharyngeal carcinoma (NPC) tumorigenesis. Their expression patterns were analyzed in a more quantitative manner at transcript level. Their protein expression levels were also investigated. We showed results that are contrary to previous report. Rather than downregulation, these genes were significantly overexpressed in NPC cell lines compared to normal control at both transcript and protein levels. Nevertheless, their association with NPC has been established. Immunoprecipitation pulldown assays indicate the plausible interaction of either RPeL27 or RPeL43 with POTEE/TUBA1A and ACTB/ACTBL2 complexes. In addition, RPeL43 is shown to bind with MRAS and EIF2S1 proteins in a NPC cell line (HK1). Our findings support RPeL27, RPeL41, and RPeL43 as potential markers of NPC and provide insights into the interaction targets of RPeL27 and RPeL43 proteins.
Fulltext Effectiveness of the use of internet search by third year medical students to establish a clinical diagnosis

Nalliah S, Chan SL, Ong CL, Suthan TH, Tan KC, She VN, et al.

Singapore Med J, 2010 Apr;51(4):332-8.
PMID: 20505913

Internet search has been the main source for information and data mining in medical research. Its use by medical students has immensely contributed to learning activities. The main aim of the study was to determine the effectiveness of internet use by medical students during their initial years of clinical instruction in order to establish a diagnosis after being provided with the history and physical findings of a clinical problem.
Nuclear magnetic resonance structure and IgE epitopes of Blo t 5, a major dust mite allergen

Chan SL, Ong TC, Gao YF, Tiong YS, Wang de Y, Chew FT, et al.

J Immunol, 2008 Aug 15;181(4):2586-96.
PMID: 18684949

A high incidence of sensitization to Blomia tropicalis, the predominant house dust mite species in tropical regions, is strongly associated with allergic diseases in Singapore, Malaysia, and Brazil. IgE binding to the group 5 allergen, Blo t 5, is found to be the most prevalent among all B. tropicalis allergens. The NMR structure of Blo t 5 determined represents a novel helical bundle structure consisting of three antiparallel alpha-helices. Based on the structure and sequence alignment with other known group 5 dust mite allergens, surface-exposed charged residues have been identified for site-directed mutagenesis and IgE binding assays. Four charged residues, Glu76, Asp81, Glu86, and Glu91 at around the turn region connecting helices alpha2 and alpha3 have been identified to be involved in the IgE binding. Using overlapping peptides, we have confirmed that these charged residues are located on a major putative linear IgE epitope of Blo t 5 from residues 76-91 comprising the sequence ELKRTDLNILERFNYE. Triple and quadruple mutants have been generated and found to exhibit significantly lower IgE binding and reduced responses in skin prick tests. The mutants induced similar PBMC proliferation as the wild-type protein but with reduced Th2:Th1 cytokines ratio. Mass screening on a quadruple mutant showed a 40% reduction in IgE binding in 35 of 42 sera of atopic individuals. Findings in this study further stressed the importance of surface-charged residues on IgE binding and have implications in the cross-reactivity and use of Blo t 5 mutants as a hypoallergen for immunotherapy.
Positive Hepatitis B Core Antibody Is Associated With Cirrhosis and Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

Chan TT, Chan WK, Wong GL, Chan AW, Nik Mustapha NR, Chan SL, et al.

Am J Gastroenterol, 2020 06;115(6):867-875.
PMID: 32149781 DOI: 10.14309/ajg.0000000000000588

OBJECTIVES: Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD).
METHODS: This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection.
RESULTS: In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity.
DISCUSSION: Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.
Study protocol for a Prospective, Randomized controlled trial of stEnt graft and Drug-coated bAlloon Treatment for cephalic arch stenOsis in dysfunctional arteRio-venous fistulas (PREDATOR)

Gan CC, Tan RY, Delaney CL, Puckridge PJ, Pang SC, Tng ARK, et al.

J Vasc Access, 2022 Nov 03.
PMID: 36330556 DOI: 10.1177/11297298221130897

BACKGROUND: Treatment of cephalic arch stenosis (CAS) is associated with high risk of failure and complications. Although stent-graft (SG) placement has improved patency rates, stent edge restenosis has been raised as a potential limiting factor for SG usage in CAS. This study aims to evaluate the safety and efficacy of combining stent graft placement with paclitaxel-coated balloon (PCB) angioplasty versus PCB alone in the treatment of CAS.
METHODS: This is an investigator-initiated, prospective, international, multicenter, open-label, randomized control clinical trial that plans to recruit 80 patients, who require fistuloplasty from dysfunctional arteriovenous fistula (AVF) from CAS. Eligible participants are randomly assigned to receive treatment with SG and PCB or PCB alone in a 1:1 ratio post-angioplasty (n = 40 in each arm). Randomization is stratified by de novo or recurrent lesion, and the participants are followed up for 1 year. The primary endpoints of the study are target lesion primary patency (TLPP) and access circuit primary patency (ACPP) rates at 6-months. The secondary endpoints are TLPP and ACPP at 3- and 12-month; target lesion and access circuit assisted primary and secondary patency rates at 3, 6, and 12-months and the total number of interventions; complication rate; and cost-effectiveness.
DISCUSSION: This study will evaluate the clinical efficacy and safety of combination SG and PCB implantation compared to PCB alone in the treatment of CAS for hemodialysis patients.
Fulltext Utility of combining PIVKA-II and AFP in the surveillance and monitoring of hepatocellular carcinoma in the Asia-Pacific region

Kim DY, Toan BN, Tan CK, Hasan I, Setiawan L, Yu ML, et al.

Clin Mol Hepatol, 2023 Apr;29(2):277-292.
PMID: 36710606 DOI: 10.3350/cmh.2022.0212

Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers.
Fulltext Recommendations for the use of next-generation sequencing in patients with metastatic cancer in the Asia-Pacific region: a report from the APODDC working group

Loong HH, Shimizu T, Prawira A, Tan AC, Tran B, Day D, et al.

ESMO Open, 2023 Aug;8(4):101586.
PMID: 37356359 DOI: 10.1016/j.esmoop.2023.101586

INTRODUCTION: Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers.
METHODS: The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration.
RESULTS: The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC.
CONCLUSION: This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective.