My research is focused on developing and validating biomarkers for cancer susceptibility, cancer progression, and therapy response, and applying these biomarkers in cutting-edge molecular epidemiology studies.† Over the years at M.D. Anderson, I have been actively involved in research and teaching activities, leading to many high-impact publications and receiving federal funding for several large studies.†
Biomarkers of Susceptibility and Progression†
My laboratory has established and applied novel biomarkers of cancer risk, including the mutagen sensitivity assay to reflect DNA repair capacity, fluorescent in situ hybridization to identify hotspots for tobacco carcinogen-induced DNA damage, and the novel Comet Assay to measure DNA damage/repair.† I also developed and refined assays to characterize cell cycle control, apoptosis, telomere, and telomerase pathways.† Additionally, my laboratory has established a panel of genetic polymorphism markers in genes related to DNA repair, carcinogen metabolism, and cell cycle control.† The ultimate goals of my research are: 1) To provide a risk assessment model which integrates genetic and environmental information obtained from my research, and identify high-risk subgroups for tobacco-related cancers, thus rationalizing intensive screening and chemopreventive interventions for high-risk populations;† 2) To provide a pharmacogenetic profile for each cancer patient and identify those patients with favorable response to a certain therapeutic modality.† The clinical benefit of this genetic profiling is to provide a basis for tailored therapy if patients are especially responsive to a certain therapy.† I will give a few examples of my current research projects and their importance toward my ultimate goals.
Mutagen Sensitivity:† One area of my research is to examine markers of genetic instability as cancer risk predictor. The level of genetic instability is measured by mutagen sensitivity assay, which is done in a laboratory culture test by "challenging" the blood samples with gamma radiation and with a carcinogenic metabolite associated with cigarette smoke to see if the cells could efficiently repair cell DNA damage. The ability to fix errant changes in DNA is of critical importance to maintain normal genetic structure, and this capability varies among individuals.† In a series of pioneering work, I demonstrated that mutagen sensitivity is a promising cancer susceptibility marker (Wu et al., Cancer Epidemiol Biomarkers Prev, 1996), playing a major role in lung cancer risk (Wu et al., Cancer Epidemiol Biomarkers Prev, 1995).† A panel of mutagen sensitivity assays would improve the risk prediction (Wu et al., Cancer, 1998; Wu et al., J Natl Cancer Inst, 1998; Wu et al., Cancer Epidemiol Biomarkers Prev, 1998).†† I further demonstrated that mutagen sensitivity also plays a role in premalignant lesions, such as oral premalignant lesions (Wu et al., Cancer Res, 2002).† In addition, using a the novel, sensitive, and rapid Comet Assay for detecting DNA strand breaks or the DNA repair capacity in individual cells, we found that latent genetic instability is associated with an increased risk of bladder cancer (J Natl Cancer Inst, 2003).† Moreover, there is a gene-diet interaction. Individuals who are especially susceptible to genetic damage to their cells and who do not eat enough dietary folate are almost three times as likely to develop bladder cancer as are those who eat plenty of fruits and vegetables and who have efficient capacity to repair DNA damage. The findings may have important implications for cancer prevention in the general population. A good practice to lower cancer risk would be to limit exposure to DNA damaging agents (cigarette smoking, UV light, etc), and to eat foods containing folates and folic acid, such as fruits and vegetables, or take a daily supplement of folic acid, to reduce the risk of developing cancer.
Telomere Length: The integrity of the human genome is also maintained in part by the architecture of telomeres. Chromosomes are tightly bundled x- and y-shaped structures in the nucleus of the cell nucleus and contain all genetic material. Like the aglet of a shoelace, telomeres form the ends of the chromosomes and protect chromosomes from eroding or degradation.† Recently, my lab developed a novel assay to measure telomere length, and demonstrated that people with shorter telomeres are at a higher risk of developing smoking-related cancers, such as lung cancer and bladder cancer. Moreover, factors such as age, gender, and smoking status appeared to influence the effect that short telomeres had on cancer risk. For example, people who smoked and had short telomeres had a substantially greater risk for tobacco-related cancers than people who never smoked and had short telomeres, or people who smoked but had longer telomeres (Wu et al., J Natl Cancer Inst, 2003).† This work has been acclaimed as a significant contribution in the field of cancer research and was reported by USA today and several other news agencies.†
Insulin-like Growth Factors (IGFs): IGF-I is an indicator of cell growth capability.† We demonstrated that there is a joint effect between mutagen sensitivity and high proliferation potential in lung cancer risk.† We were the first to show that plasma IGF-I was a predictor of lung cancer risk (J Natl Cancer Inst, 1999).† There is a joint effect of genetic instability and IGF in lung cancer risk: individuals who have high mutagen sensitivity together with a higher plasma level of IGF-I had a 26-fold increased risk for lung cancer (Wu et al., J Natl Cancer Inst, 2000).† This work has been cited as an especially important work in the field.
Single Nucleotide Polymorphisms (SNPs): Cancer risk is driven by carcinogen exposure and inherited or acquired genetic factors. Inherited genetic susceptibility factors, for example, mutated gene or allele variance, will modulate the effects of carcinogens on human cancer risk. The majority of human cancers are not hereditary but sporadic, which are caused by the combination of multiple genetic and environmental factors rather than a single specific gene or carcinogen. There are millions of small variations in DNA sequences, called single nucleotide polymorphism (SNP), among humans.† Many of these SNPs are located within functional regions of important genes, such as DNA repair genes, and cause defects in normal cellular functions.† A specific allele variant will not cause cancer by itself but contributes to cancer risk, and can affect large proportions of the population. Multiple polymorphic sites in an individual could act in concert to increase risk.† The investigation of SNPs will not only provide clues to the role of genetic risk factors in nonhereditary cancer and identify high-risk population, but also will have significant impact in pharmacogentics, i.e., provide guidance for tailored therapy.† We have demonstrated that the variant alleles of many important genes, such as tumor suppressor p53, death receptor gene DR4, DNA repair gene XRCC, XPD, etc., play an important role in susceptibility to tobacco-induced cancers (Cancer Res, 2001, Wu et al., J Natl Cancer Inst, 2002, Cancer Res, 2003).† We will continue to exploit in this area utilizing a newly created high-throughput genotyping core directed by myself.† More emphasis will be on collective effects of gene-gene interactions and gene-environment interactions.†
Teaching Activities and Administrative/Service Roles:
In addition to supervising more than 20 research personnel, I have served as a mentor for a junior faculty memberís K12 grant, a junior faculty memberís KO7 grant, an advisor or chairman of thesis supervisory committees for 19 Ph.D and masters students, an advisory committee member for 6 graduate students, and a mentor for 2 clinical fellows, 7 postdoctoral fellows, 3 NIOSH residence fellows, 5 NCI short-term fellows, and 3 high school or college students. Beginning in the fall of 1999, I have been the primary instructor for the Molecular Epidemiology course at the The University of Texas School of Public Health (UTSPH). This course has been expanded to Graduate School of Biomedical Sciences (GSBS) and broadcasted to affiliated schools in Dallas, Brownsville, and San Antonio. The average size of the class is 35 enrolled graduate students.† Additionally, I serve as a guest lecturer in graduate level courses at UTSPH and UTGSBS. I also serve as a reviewer for numerous journals and a member of several Scientific Review Committees.
Our team has become one of the leading groups in cancer susceptibility research. I intend to continue developing novel genotypic and phenotypic markers for cancer susceptibility and build a practical model for cancer risk assessment.† I also plan to expand our research to phamacogenetics. It is estimated that genetic factors account for 20 to 95 percent of variability in drug disposition and effects. The central aim of pharmacogenetics is the prediction of responders and non-responders to certain drugs, and the identification of individuals at risk for adverse drug reactions based on the knowledge of variations in relevant genes. We will focus on the identification of functionally important variations in genes coding for drug-metabolizing enzymes, and drug transporters or receptors.† The ultimate goal is to provide a genetic basis for tailored therapy.