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
member’s K12 grant, a junior faculty member’s 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.
Future Goals:
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.