Transcript UCLA`s Jonsson Comprehensive Cancer Center Program Area Name

UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing)
Zuo-Feng Zhang, M.D., Ph.D., Director
Curtis Eckert, Ph.D., Associate Director
Alper Symposium of
Molecular Epidemiology of
Lung and Other SmokingRelated Cancers
UCLA Department of Epidemiology
School of Public Health
April, 14, 2007
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing)
Program Mission:
To develop a multidisciplinary molecular epidemiologic approach using the newly
developed technologies to understand gene-environment interactions that may
alter the risk and progression of cancer and to apply the knowledge to cancer
risk assessment (primary prevention), early detection (secondary prevention)
and prognosis prediction (tertiary prevention).
Scientific Themes:
First theme: Primary prevention: Environmental exposure (smoking, diet, infection, air
pollution, etc.) and genetic susceptibility-based cancer risk assessment and
gene-environmental interactions on the risk of cancers.
Second theme: Secondary prevention: Biological markers for early detection and
intermediate markers as surrogate end-points for chemoprevention.
Third theme: Tertiary prevention: Blood and tissue-based biological markers for
cancer prognosis prediction.
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing)
Number of Members: 18
NCI Funding (N=9):$2.2 M
Other Federal Peer Reviewed Funding (N=22):$5.4 M
Other Funding (N=22):$4.0 M
Total Funding:$11.6 M
Cancer Publications: 123
Interprogrammatic: 17%
Intraprogrammatic: 12%
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing)
Platforms for Activities
Monthly Seminar Series on Molecular Epidemiology, Molecular
Toxicology, and Genomics and Nutrition. Monthly DCPCR
Monthly Teas to discuss mutual research interests with other
programs within DCPRC
Yearly Meeting/Retreats on Molecular Epidemiology, GeneEnvironment Interaction on Cancer. Bi-annual Alper-JCCC
Symposium on Environmental Genomics and Risk of Cancer
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing):
Susceptibility Markers for Primary Prevention
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We have assayed over 150 genetic polymorphisms of genes in
the metabolic, inflammatory, cell cycle control, DNA repair
pathways
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Among 4,000 study subjects with cancers of seven sites
including lung, head and neck, esophagus, stomach, liver,
prostate, and bladder,
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Using high through-put genotyping platform – ABI SNPlex
(JCCC Genotyping Core). An additional 200-300 SNPs will be
assayed among 4,000 study subjects.
Theoretical model of gene-environmental interaction pathway for cancer susceptibility
Tobacco/alcohol
infection
Environmental Carcinogens /
Procarcinogens Exposures
Ile105Val 
Ala114Val
Diet and nutritional
factors
Null 
GSTP1
GSTM1
CYP2E1
Nitrosemins,
Xenobiotics,
Diet/nutrient
Tyr113His
His139Arg
mEH
Detoxified
carcinogens
Active carcinogens
Pro187Ser
Diet/nutrient
Free radicals
Oxidative Stress
mEH
NQO1
DNA damage
repaired
DNA Damage
Tyr113His
His139Arg
Normal cell
Defected DNA
repair gene
If DNA damage not
repaired
XRCC3
M
G1
G2
P53
Arg72Pro
P16
G0
S
G870A
Ala146Thr
Cyclin D1
If loose cell cycle
control
Carcinogenesis
Programmed cell
death
Joint effect of tobacco smoking and XPG polymorphism on lung
cancer risk
25
Departure from additivity:
23-13-1.9+1=9.1, 95% CL=-2.9, 21.7
20
15
10
5
0
Pack-years:
XPG:
Never
1-20
>20
Never
Asp/Asp
Asp/Asp
Asp/Asp
His/His +His/Asp
1-20
His/His +His/Asp
>20
His/His +His/Asp
Cui Y, Morgenstern H, Greenland S, Tashkin DP, Mao J, Cao W, Cozen W,
Mack TM, Zhang ZF. Polymorphism of Xeroderma Pigmentosum group G and
the risk of lung cancer and squamous cell carcinomas of the oropharynx,
larynx and esophagus. Int J Cancer. 2006 Feb 1;118(3):714-20.
Joint effect of tobacco, alcohol, and XPG polymorphism on
SCCUAT
18
16
14
12
10
8
6
4
2
0
Drinks per day:
1-2
1-2
>=3
>=3
1-2
1-2
>=3
>=3
Packyears:
<=20
<=20
<=20
<=20
>20
>20
>20
>20
His/His +His/Asp
Asp/Asp
His/His +His/Asp
XPG:
Asp/Asp
His/His +His/Asp
Asp/Asp
His/His +His/Asp
Asp/Asp
Cui Y, Morgenstern H, Greenland S, Tashkin DP, Mao J, Cao W, Cozen W,
Mack TM, Zhang ZF. Polymorphism of Xeroderma Pigmentosum group G and
the risk of lung cancer and squamous cell carcinomas of the oropharynx,
larynx and esophagus. Int J Cancer. 2006 Feb 1;118(3):714-20.
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing):
Secondary Prevention: Markers for Early
Detection/Chemoprevention
-Epidemiological study of green tea
drinking and risk of cancers
-Gene-green tea interaction on risk of
cancers
-Proteomics approach to identify potential
target for the effect of green tea, using
JCCC Proteomics Core.
Mu LN, Lu QY, Yu SZ, Jiang QW, Cao W, You NC, Zhou XF, Ding BG, Wang RH,
Zhao J, Cai L, Rao JY, Heber D, Zhang ZF. Green tea and its interactions with
other risk factors on the risk of stomach cancer in a Chinese population.
International Journal of Cancer 2005; 116: 972-83.
Xiao GS, Jin YS, Lu QY, Zhang ZF, Belldegrun A, Figlin R, Pantuck A, Yen Y, Li
F, Rao J. Annexin-I as a potential target for green tea extract induced actin
remodeling. Int J Cancer. 2007 Jan 1;120(1):111-20.
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing): Markers for
Progression
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p53 is an independent predictor of tumor recurrence and progression after nephrectomy in
patients with localized renal cell carcinoma. Shvarts O, Seligson D, Lam J, Shi T, Horvath S,
Figlin R, Belldegrun A, Pantuck AJ. J Urol 2005;173(3):725.
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Reg IV: a promising marker of hormone refractory metastatic prostate cancer. Gu Z, Rubin
MA, Yang Y, Deprimo SE, Zhao H, Horvath S, Brooks JD, Loda M, Reiter RE. Clin Cancer
Res 2005;11(6):2237.
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Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma.
Kim HL, Seligson D, Liu X, Janzen N, Bui MH, Yu H, Shi T, Belldegrun AS, Horvath S, Figlin
RA. J Urol 2005;173(5):1496.
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Prostate stem cell antigen is overexpressed in prostate cancer metastases. Lam JS,
Yamashiro J, Shintaku IP, Vessella RL, Jenkins RB, Horvath S, Said JW, Reiter RE. Clin
Cancer Res 2005;11(7):2591.
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Global histone modification patterns predict risk of prostate cancer recurrence. Seligson DB,
Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK. Nature 2005;435(7046):1262.
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Tumor classification by tissue microarray profiling: random forest clustering applied to renal
cell carcinoma. Shi T, Seligson D, Belldegrun AS, Palotie A, Horvath S. Mod Pathol
2005;18(4):547.
Bladder Tissue Array
HE
Yang YC, Lu ML, Rao JY, Wallerand H, Cai L, Cao W, Pantuck A, Dalbagni G,
Reuter V, Figlin RA, Belldegrun A, Cordon-Cardo C, Zhang ZF. Joint association
of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder
cancer prognosis. Br J Cancer. 2006 Dec 4;95(11):1455-8.
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing)
Clinical Research
# of Trials: N/A
# of High Priority Clinical Trials: N/A
Total # of Patient Accruals: N/A
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing)
Role of the Cancer Center
Space: Hankinson, Rao, ^Zhang
Funding (Seed, Interdisciplinary): $70k
Faculty recruitment/retention: Liu (Simin)
Use of shared resources: Flow Cytometry, Gene
Expression, Tissue Procurement, Molecular
Screening, Genotyping
^ indicates listing in two program areas
UCLA’s Jonsson Comprehensive Cancer Center
Molecular Epidemiology (Developing)
Future Plans and Goals
-Enhance the molecular epidemiology and
gene-environment interaction research and
training.
-Continue the research into molecular
epidemiology and gene-environment
interaction on risk of cancers using cuttingedge technology
-Foster multidisciplinary approaches and
collaborations between program faculty.