Joint Appointments:
Associate Professor,
Department of Biochemistry,
National University of Singapore
Associate Professor, Duke-NUS
Graduate Medical School
Research Staff
Yi Wei LU (PhD), Zihua WANG, Jianwei REN, Yu WANG, JingBo WANG, Pui Hoon SEW
Clinical Attachment
Grace PANG (MBBS)
Selected Publications
Lee CG, Ren J, Cheong IS, Jin R, Ban KH, Ooi LL, Nuchprayoon I, Lee KH, Choti M, Lee LA
Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers. Oncogene (2003) 22(17):2592-2603.
Tang K, Wong LP, Lee EJ, Chong SS, Lee CG
Genomic evidence for recent positive selection at the human MDR1 gene locus. Hum. Mol. Genet. (2004) 13:783-797.
Wang Z, Wang B, Tang K, Lee EJ, Chong SS, Lee CG
A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection. Hum. Mol. Genet. (2005) 14(14):2075-2087.
Lee AT, Ren J, Wong ET, Ban KH, Lee LA, Lee CG
The hepatitis B virus X protein sensitizes HepG2 cells to UV light-induced DNA damage. J. Biol. Chem. (2005) 280(39): 33525-33535.
Ren J, Kan A, Leong SH, Ooi LL, Jeang KT, Chong SS, Kon OL, Lee CG
Fat10 plays a role in the regulation of chromosomal stability. J. Biol. Chem. (2006) 281(16):11413-11421.
Wang Z, Wang J, Tantoso E, Wang B, Tai AY, Ooi LL, Chong SS, Lee CG
Signatures of Recent Positive Selection at the ATP-Binding Cassette (ABC) Drug Transporter Superfamily Gene Loci. Hum. Mol. Genet. (In press, 2007)
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and especially so in the Asia Pacific region. Our laboratory’s key research goal is to elucidate the molecular pathway(s) leading to HCC. Using a cDNA microarray approach, we have identified several genes that are significantly differentially expressed between the tumour and adjacent normal tissues and are in the process of characterizing some of them.
I. Functional Genomics of Hepatocellular Carcinoma
Interestingly, we found that cells over-expressing one of these genes escape mitotic arrest and have more variable chromosome numbers per cell. We hope that this gene or other novel genes identified through cDNA microarray approach will serve as:
prognostic markers, or
markers to identify individuals who are at high risk of developing HCC, or
markers to identify individuals at high risk of having recurrence of the tumour in HCC patients. We also hope that target-specific therapies can be developed with the identification of the pathway(s) responsible for HBV-associated HCC.
Infection by the Hepatitis B virus HBV is predominant in HCC patients in this part of the world. Hence, another research focus of our lab is to examine the role that HBx, a protein in HBV, plays in the carcinogenesis process.
II. Genetics of Drug Response Genes
Differences in drug response between individuals can be due to pharmacokinetic as well as pharmacodynamic variations. As 90% of inter-individual variation consists of single nucleotide polymorphisms (SNPs), SNPs are now commonly examined in the area of population genetics, complex disease associations as well as pharmacogenetics.
Thus far, although the majority of pharmacogenetic variations were studied in drug metabolizing enzymes, there is an increasing interest in examining pharmacogenetic variations due to differences in receptor affinity, drug transporters, drug uptake and excretion processes.
Hence, another interest of our lab is to fully characterize the SNPs, haplotype and linkage-disequilibrium profiles of drug response genes including drug transporters, drug metabolizing enzymes, regulators and drug targets in the different ethnic populations in Singapore compared to the Caucasians and African Americans.
We will also try to identify functionally important polymorphisms that will be useful for association studies.
Our approach of identifying functional polymorphisms will be based on principles of natural selection and “survival of the fittest”.
The exodus of mankind from Africa exposed our ancestors to new and different environments and diseases. Polymorphisms in genes that facilitate better adaptation of the individual to the new environment will be retained and have its frequency increased in that population while polymorphisms that are deleterious will be removed and its frequency reduced in that population.
These “signatures of natural selection” left behind in our genome can be utilized to identify functionally important polymorphisms in “adaptive” genes that play a role in enabling the individual to adapt to new environments.
We are also in the process of developing a user-friendly cost-effective chip to facilitate the genotyping of these positively selected SNPs so that it can be more readily brought into the clinic. Our ultimate goal is to be able to tailor an individual’s drug regimen to his genetic profile so that drugs can be delivered at the optimal dose with maximum efficacy and minimum adverse effects.
