Tobacco Carcinogen and Toxicant
Biomarkers
Stephen S. Hecht, Ph.D.
Masonic Cancer Center
University of Minnesota
Outline of Presentation
• Tobacco and cancer
• Background on tobacco carcinogen
biomarkers
• Examples of tobacco carcinogen
biomarkers
– Total NNAL
– Formaldehyde-DNA adducts
Cancers Caused by Smoking:
IARC Monograph Series
Volume 38, 1986
• Lung
• Oral cavity
• Pharynx
• Larynx
• Esophagus
• Pancreas
• Bladder
Volume 83, 2004, added:
• Nasal Cavity
• Stomach
• Liver
• Kidney
• Ureter
• Cervix
• Myeloid leukemia
Volume 100E, 2009, added:
• Colorectum
• Ovary (mucinous)
Cancer Deaths Due to Smoking
• Worldwide: 21% (1,420,000 per year)
• United States: 33% (185,000 per year)
IARC World Cancer Report, 2008
Tobacco Use Prevalence, 2008
• Adult smokers, U.S.: 46,000,000 (20.6%)
• Ex-smokers, U.S.: 48,100,000 (21.5%)
• Smokers, worldwide: 1,300,000,000
• Smokeless, worldwide: xxx,000,000
CDC, MMWR, November 13, 2009
World Smoking Prevalence: Males
O. Shafey, M. Ericksen, H. Ross, J. Mackay (2009) The Tobacco Atlas, 3rd Ed.
World Smoking Prevalence: Females
O. Shafey, M. Ericksen, H. Ross, J. Mackay (2009) The Tobacco Atlas, 3rd Ed.
Overall Goal
Elucidate mechanisms of
tobacco-induced cancer and apply this
knowledge to cancer prevention.
Conceptual Framework for Understanding
Tobacco Carcinogenesis
S.S. Hecht, JNCI, 91:1194-1210 (1999), Nature Rev. Cancer 3:733-744 (2003); Cancer: Principles and
Practice of Oncology, 8th Edition, 147-155 (2008)
Significantly Mutated Genes in Lung Adenocarcinoma:
Based on Sequencing of 623 Genes in 188 Tumors
Ding et al, Nature, 455:1069-1075, 2008
Other Factors Contributing to
Tobacco-Induced Cancer
•
•
•
•
•
•
•
Receptor mediated effects:nicotine, nitrosamines
Direct activation of EGFR and COX-2
Down-regulation of FHIT
Hyper-methylation of tumor suppressors
Tumor promotion and co-carcinogenesis
Oxidative damage and inflammation
Cilia-toxicity
H. Takahashi et al, Cancer Cell 17: 89 (2010); H. Schuller, Nature Rev. Cancer 9: 195-205 (2009); K.A.
West et al, J. Clin. Invest. 111: 81-90 (2003); S.A. Belinsky, Carcinogenesis 26: 1481 (2005); D’Agostini et
al, Cancer Res 66: 3936-3941 (2006); Jin et al, Carcinogenesis 29: 1614-1622 (2008); Bhutani et al, Cancer
Prev. Res. 1: 39-44 (2008)
Conceptual Framework for Understanding
Tobacco Carcinogenesis
S.S. Hecht, JNCI, 91:1194-1210 (1999), Nature Rev. Cancer 3:733-744 (2003); Cancer: Principles and
Practice of Oncology, 8th Edition, 147-155 (2008)
IARC Carcinogens in Tobacco Smoke
Chemical class
PAH
No. of compounds
16
Nitrosamines
Aromatic amines and
heterocyclic aromatic
amines
8
13
Aldehydes
2
Volatile hydrocarbons
6
Other organics
Inorganic compounds
Total
Representative carcinogens
18
9
72
S.S. Hecht, In: DeVita et al, Cancer (2010); IARC Monographs No. 83 (2004);
D. Hoffmann and S.S. Hecht, Handbook Exp. Pharmacol. 94:63-102 (1990)
Goal
• Develop and validate tobacco carcinogen
and toxicant biomarkers
– Urinary metabolites
– DNA and protein adducts
– Metabolites in blood, saliva, breath, nails, hair
• Use these biomarkers to identify those
smokers susceptible to cancer.
Outline of Presentation
• Tobacco and cancer
• Background on tobacco carcinogen
biomarkers
• Examples of tobacco carcinogen
biomarkers
– Total NNAL
– Formaldehyde-DNA adducts
Definitions
• Biomarker: A distinctive biological or
biologically derived indicator (as a metabolite)
of a process, event, or condition
(Merriam-Webster’s Collegiate Dictionary)
• Tobacco carcinogen biomarker: Any
quantifiable substance, such as a metabolite,
that can be specifically related to human
exposure to a given tobacco carcinogen.
Tobacco Carcinogen Biomarkers
• DNA Adducts
• Protein Adducts
– Hemoglobin
– Albumin
• Metabolites
– Breath
– Saliva
– Nails and Hair
– Urine
– Blood
Reviewed in Carcinogenesis 23: 907 and 1979 (2002); Nature Rev. Cancer 3: 733 (2003)
Applications of Tobacco Carcinogen
Biomarkers
• Assessing exposure in smokers, smokeless
tobacco users, and non-smokers exposed to
secondhand smoke
• Regulation of tobacco products
• Understanding mechanisms of human
carcinogenesis and identifying susceptible
individuals
• Not specifically designed for early detection of
cancer, but could have applications in screening
A Panel of Tobacco Carcinogen and Toxicant Biomarkers
Range of recent mean values
(nmol/24h unless noted otherwise)
Urinary biomarkers
Source
Smokers
Non-smokers
Nicotine equivalents
Nicotine
70.4-154 µmol/24 h
Not Detected
Total NNAL
NNK
1.1 - 2.9
Not Detected
Total NNN
NNN
0.049 - 0.24
Not Detected
1-HOP or PheT
PAH
0.50 - 1.45
0.18 - 0.50
MHBMA
1,3-Butadiene
15.5 - 322
0.65 - 7.5
SPMA
Benzene
3.2 - 32.1
0.17 - 3.14
HPMA
Acrolein
5,869 - 11,190
1,131 - 1,847
HBMA
Crotonaldehyde
1,965 - 26,000
242 - 3,200
HEMA
Ethylene oxide
19.1 - 102
6.51 - 38.8
Cd
Cadmium
2.3 - 12.8
1.34 - 8.04
8-epi-PGF2a
Oxidative damage
1.48 - 2.80
0.62 - 1.13
PGE-M
Inflammation
54 - 60
31.6 - 45.3
Based on 1.3g creatinine per 24h in smokers and 1.5g creatinine per 24h in non-smokers, or 1.5 l urine per 24h.
S.S. Hecht, J-M Yuan, and D. Hatsukami, Chem. Res. Toxicol., 2010
Structures of the Urinary Biomarkers
A Panel of Biomarkers
Recent data
(pmol/g globin; mean ± S.D.)
Hemoglobin adducts
Source
Smokers
Non-smokers
Cyanoethylvaline
Acrylonitrile
112 ± 81
6.5 ± 6.4
Carbamoylethylvaline
Acrylamide
84.1 ± 41.8
27.8 ± 7.1
Hydroxyethylvaline
Ethylene oxide
132 ± 92
21.1 ± 12.7
4-Aminobiphenyl-globin
4-Aminobiphenyl
0.26 ± 0.006a
0.067 ± 0.009a
(fmol/µmol dN; mean ± S.D.)
Leukocyte DNA adducts
Source
Smokers
Non-smokers
N6-hydroxymethyl-dAdo
Formaldehyde
179 ± 205
15.5 ± 33.8
N2-ethylidene-dGuo
Acetaldehyde
1,310 ± 1,720
705 ± 438
Mean concentrations
Other
Source
Smokers
Non-smokers
Exhaled CO
Carbon monoxide
17.4 - 34.4 ppm
2.6 - 6.5 ppm
Carboxyhemoglobin
Carbon monoxide
3.4 - 7.1 %
0.35 - 1.45 %
Biomarker Validation
• Analytical
– Specificity, sensitivity, accuracy, precision
• With respect to tobacco
– Decreases upon cessation
– Dose-response
• With respect to cancer risk
Persistence of Biomarkers Study
• Smokers provide baseline 24h urine samples.
• Eight days later, they quit smoking and receive
nicotine replacement therapy.
• They provide 24h urine samples on days 3, 7, 14,
21, 28, 42, and 56 after quitting.
• Urine samples are analyzed for mercapturic acids
(by LC-MS/MS) and other biomarkers.
S.G. Carmella, M. Chen, S. Han, A. Briggs, J. Jensen, D. K. Hatsukami, and S. S. Hecht
Chem. Res. Toxicol., 22: 734-741 (2009)
Metabolism of 1,3-Butadiene to
Mercapturic Acids
a. GSH, GSTs; b. g-glutamyltranspeptidase; c. cysteinylglycine dipeptidase; d. cysteine S-conjugate N-acetyltransferase
C.L. Sprague and A.A. Elfarra, Chem. Res. Toxicol., 17: 819-826 (2004)
% R E D U C T IO N F R O M B A S E L IN E S M O K IN G
Mean Urinary MHBMA Reduction Upon Smoking Cessation, N=17
0
20
40
60
80
100
0
10
20
30
40
D A Y S P O S T C E S S A T IO N
50
60
Metabolism of Acrolein, Crotonaldehyde, Benzene,
and Ethylene Oxide to Mercapturic Acids
a. GSH, GSTs; b. g-glutamyltranspeptidase; c. cysteinylglycine dipeptidase; d. cysteine S-conjugate N-acetyltransferase
% R E D U C T IO N F R O M B A S E L IN E S M O K IN G
Mean Urinary HPMA Reduction Upon Smoking Cessation, N=17
0
20
40
60
80
100
0
10
20
30
40
D A Y S P O S T C E S S A T IO N
50
60
% R E D U C T IO N F R O M B A S E L IN E S M O K IN G
Mean Urinary HBMA Reduction Upon Smoking Cessation, N=17
0
20
40
60
80
100
0
10
20
30
40
D A Y S P O S T C E S S A T IO N
50
60
% R E D U C T IO N F R O M B A S E L IN E S M O K IN G
Mean Urinary SPMA Reduction Upon Smoking Cessation, N=17
0
20
40
60
80
100
0
10
20
30
40
D A Y S P O S T C E S S A T IO N
50
60
% R E D U C T IO N F R O M B A S E L IN E S M O K IN G
Mean Urinary HEMA Reduction Upon Smoking Cessation, N=17
0
20
40
60
80
100
0
10
20
30
40
D A Y S P O S T C E S S A T IO N
50
60
Structures of Urinary Biomarkers
S.G. Carmella, et al, Chem. Res. Toxicol., 22: 734-741 (2009)
Mean Urinary 1-HOP Reduction Upon Smoking Cessation, N=15
% R E D U C T IO N F R O M B A S E L IN E S M O K IN G
Mean Urinary Total NNAL Reduction Upon Smoking Cessation, N=17
0
20
40
60
80
100
0
10
20
30
40
D A Y S P O S T C E S S A T IO N
50
60
Outline of Presentation
• Tobacco and cancer
• Background on tobacco carcinogen
biomarkers
• Examples of tobacco carcinogen
biomarkers
– Total NNAL
– Formaldehyde-DNA adducts
A Panel of Tobacco Carcinogen and Toxicant Biomarkers
Range of recent mean values
(nmol/24h unless noted otherwise)
Urinary biomarkers
Source
Smokers
Non-smokers
Nicotine equivalents
Nicotine
70.4-154 µmol/24 h
Not Detected
Total NNAL
NNK
1.1 - 2.9
Not Detected
Total NNN
NNN
0.049 - 0.24
Not Detected
1-HOP or PheT
PAH
0.50 - 1.45
0.18 - 0.50
MHBMA
1,3-Butadiene
15.5 - 322
0.65 - 7.5
SPMA
Benzene
3.2 - 32.1
0.17 - 3.14
HPMA
Acrolein
5,869 - 11,190
1,131 - 1,847
HBMA
Crotonaldehyde
1,965 - 26,000
242 - 3,200
HEMA
Ethylene oxide
19.1 - 102
6.51 - 38.8
Cd
Cadmium
2.3 - 12.8
1.34 - 8.04
8-epi-PGF2a
Oxidative damage
1.48 - 2.80
0.62 - 1.13
PGE-M
Inflammation
54 - 60
31.6 - 45.3
Based on 1.3g creatinine per 24h in smokers and 1.5g creatinine per 24h in non-smokers, or 1.5 l urine per 24h.
S.S. Hecht, J-M Yuan, and D. Hatsukami, Chem. Res. Toxicol., 2010
Essential Facts About NNK,
A Tobacco-Specific Lung Carcinogen
• Present in tobacco and tobacco smoke; specific to
tobacco products
• Systemic lung carcinogen in rats, mice, hamsters, and
ferrets.
• Also induces tumors of the pancreas, nasal cavity, and
liver in rats
• Considered to be a cause of lung, oral cavity and
pancreatic cancer in people exposed to tobacco
products
• NNK and NNN- Carcinogenic to humans; Group 1
(IARC Volume 89, 2007); reaffirmed (Vol 100E, 2009)
S.S. Hecht, Chem. Res. Toxicol. 11:559 (1998); Nature Rev. Cancer 3:733 (2003)
Metabolism of NNK by Carbonyl Reduction
O
N
O
N
CH3
N
1 1  -H S D -1
CR
OH
N
O
N
A K R 1 C 1 ,2 ,4
CH3
U G Ts
N N A L-G lu cs
N
NNK
NNAL
N ico tin e-d e rive d
N itro sam in o K e ton e
ca rcin og e n icity sim ila r
to N N K
(R )-N N A L -O -G lu c
in a c tive
NNAL Plus NNAL-Glucs (Total NNAL):
A Biomarker of NNK Exposure
•
•
•
•
•
Quantified by GC-TEA or LC-MS/MS
High analytical specificity and sensitivity
Specific to tobacco product exposure
Responsive to dose
Measures uptake of a lung carcinogen
S.S. Hecht, Carcinogenesis 23 907 (2002); S.G.Carmella et al, CEBP 4: 635 (1995); 12: 1257 (2003);
D. Hatsukami et al, Nic. Tob. Res. 8: 169 (2006)
GC-TEA Chromatogram of NNAL in a
Smoker's Urine
Applications of the Total NNAL Biomarker
•
•
•
•
•
•
Cessation of smoking or smokeless tobacco
Reduction of smoking
Carcinogen uptake from new and old tobacco products:
– Omni, light and ultra-light cigarettes
– Snus and other smokeless products
– Ultra low nicotine cigarettes
Evaluation of carcinogen dose in various groups
– Reducers vs. light smokers
– Smokers of differing numbers of cigarettes
– Ethnic groups, gender, and teen-age smokers
– Smokeless vs. smokers
– Duration of smokeless use
Carcinogen uptake from secondhand cigarette smoke
Relationship to lung cancer
D. Hatsukami, J. Jensen, A. Joseph, S. E. Murphy, S.G. Carmella, S.S. Hecht, and co-workers.
Cancer Res., JNCI, CEBP, Nic. Tob. Res., 1999-2008
Tobacco Harm Reduction:
Continuum of Risk
Most toxic
Conventional cigarettes
Modified tobacco cigarettes
Cigarette reduction
Cigarette-like delivery devices;
Extra-low nicotine cigarettes
Smokeless tobacco products
Least toxic
Nicotine delivery devices
Smoking Cessation
D. Hatsukami et al., Nicotine Tob. Res. 9:S537-S553 2007
Applications of the Total NNAL Biomarker
•
•
•
•
•
•
Cessation of smoking or smokeless tobacco
Reduction of smoking
Carcinogen uptake from new and old tobacco products:
– Omni, light and ultra-light cigarettes
– Snus and other smokeless products
– Ultra low nicotine cigarettes
Evaluation of carcinogen dose in various groups
– Reducers vs. light smokers
– Smokers of differing numbers of cigarettes
– Ethnic groups, gender, and teen-age smokers
– Smokeless vs. smokers
– Duration of smokeless use
Carcinogen uptake from secondhand cigarette smoke
Relationship to lung cancer
D. Hatsukami, J. Jensen, A. Joseph, S. E. Murphy, S.G. Carmella, S.S. Hecht, and co-workers.
Cancer Res., JNCI, CEBP, Nic. Tob. Res., 1999-2008
Non-Smokers’ Exposure to NNK Throughout Life by
Measurement of Urinary Total NNAL
Type of Exposure
Total NNAL
(fmol/ml urine)
% of Amount in
Smokers' Urinea
Fetus
Transplacental
25 ± 29
(amniotic fluid)
1.3
Newborns
Transplacental
130 ± 150
6.5
Air
83 ± 20
4.2
Minneapolis
Air
56 ± 76
2.8
Moldova
Air
90 ± 77
4.5
Women Living
with Smokers
Air
50 ± 68
2.5
Hospital Workers
Air
59 ± 28
3.0
Casino Patrons
Air
18 ± 15
0.9
Restaurant and
Bar Workers
Air
33 ± 34
1.7
Exposed Group
Infants (<1 year old)
Elementary School Children
a
based on 2 pmol/ml total NNAL in smokers
S.S. Hecht, Carcinogenesis 23:907 (2002); S.S. Hecht et al, CEBP 15:988 (2006)
Total NNAL measurements in
secondhand smoke-exposed nonsmokers have impact
•
•
•
•
It can only come from secondhand smoke.
It represents uptake of a lung carcinogen.
It is found in the urine of non-smokers.
It is the only lung carcinogen biomarker consistently
elevated in exposed non-smokers.
• These studies should spur clean air legislation in
the remaining countries, states and localities.
Median Serum Cotinine Levels in
Non-Smokers, by Age Group: 1988-2002
CDC NHANES Study; MMWR 55: 1130 (2006)
Regulation of Indoor Smoking and
Tobacco Control
• Regulation of indoor smoking
– Reduces cues for smoking
– Reduces amount smoked
– Can change social norms
• Regulation of indoor smoking, along with
counter-advertising and taxation, are the
most effective methods in tobacco control.
Applications of the Total NNAL Biomarker
•
•
•
•
•
•
Cessation of smoking or smokeless tobacco
Reduction of smoking
Carcinogen uptake from new and old tobacco products:
– Omni, light and ultra-light cigarettes
– Snus and other smokeless products
– Ultra low nicotine cigarettes
Evaluation of carcinogen dose in various groups
– Reducers vs. light smokers
– Smokers of differing numbers of cigarettes
– Ethnic groups, gender, and teen-age smokers
– Smokeless vs. smokers
– Duration of smokeless use
Carcinogen uptake from secondhand cigarette smoke
Relationship to lung cancer
D. Hatsukami, J. Jensen, A. Joseph, S. E. Murphy, S.G. Carmella, S.S. Hecht, and co-workers.
Cancer Res., JNCI, CEBP, Nic. Tob. Res., 1999-2008
Relationship of Urinary NNAL to Lung Cancer in
Two Prospective Cohorts of Cigarette Smokers
• Collaboration with Professors Mimi Yu and
Jian-Min Yuan
• Two prospective cohorts of Chinese cigarette
smokers: Shanghai and Singapore
• Nested case control study of 246 cases of lung
cancer and 245 matched controls
• Total NNAL and cotinine quantified in stored urine
samples collected prior to lung cancer diagnosis
Joint Effect of Urinary Total NNAL and
Cotinine on Lung Cancer Risk
Cotinine in tertile
NNAL in
tertile
1st (low)
Ca/Co1
OR (95% CI)2
2nd
3rd (high)
Ca/Co1
OR (95% CI)2
Ca/Co1
OR (95% CI)2
1st (low)
9/47
1.00
23/25
3.93 (1.54, 10.05)
11/10
5.08 (1.63, 15.89)
2nd
14/24
3.01 (1.11, 8.10)
31/32
4.15 (1.70, 10.12)
22/26
4.48 (1.78, 11.31)
3rd (high)
8/10
3.41 (1.08, 11.25)
30/25
5.58 (2.25, 13.84)
93/46
8.47 (3.69, 19.46)
1
No. of cases/no. of controls
2
Odds ratios (OR) were adjusted for age, year of interview, year of sample collection, gender and dialect group, study location
(Shanghai versus Singapore), number of cigarettes smoked per day, and number of years of smoking; CI, confidence interval.
J. Yuan, M. Yu, S.E. Murphy, S. Carmella, S.S. Hecht et al., Cancer Res.,69: 2990 (2009)
Conclusions of the Shanghai and
Singapore Study
• Total NNAL significantly associated with risk of
lung cancer in a dose-dependent manner, after
adjustment for smoking history and urinary
cotinine.
• Cotinine was independently associated with lung
cancer, consistent with previous data.
• Smokers in the highest tertiles of urinary total
NNAL and cotinine exhibited an 8.5 fold
increased risk for lung cancer, relative to those
with comparable smoking history, but in the
lowest tertiles.
J. Yuan et al, Cancer Res. 69: 2990 (2009)
Similar Results in the PLCO Study
• The Prostate, Lung, Colon, and Ovarian Cancer Screening
Trial: started 1993
• 77,468 subjects (25,000 smokers) screened; over 1,000
lung cancer cases diagnosed
• Questionnaire data and blood samples collected
prospectively
• 100 lung cancer cases and 100 controls without lung
cancer selected – all were smokers of > 10 CPD
• Pre-diagnostic serum analyzed for total NNAL and cotinine
T. Church, K. Anderson, M. Geisser, Y. Zhong, C. Le, N. Caporaso, S. Carmella,
A. Benoit, S. S. Hecht, CEBP,18: 260 (2009)
Total NNAL and Lung Cancer
• Total NNAL is a risk biomarker.
• Results are consistent with all experimental
and previous clinical and epidemiologic data.
• Results further implicate NNK as an
independent etiologic risk factor in lung
cancer.
Cigarette Smoke Constituents Targeted for
Regulation by WHO, and Their Biomarkers
•
•
•
•
•
•
•
•
•
Benzo[a]pyrene
NNK, NNN
Acrolein
Benzene
1,3-Butadiene
Carbon monoxide
Acetaldehyde
Formaldehyde
Nicotine
•
•
•
•
•
•
•
•
•
1-HOP or PheT in urine
NNAL and NNN in urine
3-HPMA in urine
SPMA in urine
MHBMA in urine
Exhaled CO
Leukocyte DNA adducts
Leukocyte DNA adducts
Nicotine metabolites
D.M. Burns et al. Tob. Control. 17: 132-141 (2008); S.S. Hecht, Carcinogenesis 23: 907-922 (2002); L. Chen
et al. Chem. Res. Toxicol. 20: 108-133 (2007); S.G. Carmella et al. Chem. Res. Toxicol., 22: 734-741 (2009)
Outline of Presentation
• Tobacco and cancer
• Background on tobacco carcinogen
biomarkers
• Examples of tobacco carcinogen
biomarkers
– Total NNAL
– Formaldehyde-DNA adducts
Formaldehyde – Genetic Toxicology
• Genotoxic
– Mutagenic
– DNA protein cross-links
– DNA strand breaks
– Sister chromatid exchanges
– Chromosomal aberrations
• These changes initiated by reactions with DNA to form
adducts
• No previous reports of formaldehyde DNA adducts in
humans
International Agency for Research on Cancer Monographs, Volume 88 (2006)
Structures of Formaldehyde-DNA Adducts
R. Shapiro et al. (1980); F. Beland et al. (1984)
Conversion of N6-HOMe-dAdo to N6-Me-dAdo
M. Wang et al. Chem. Res. Toxicol. 20: 1141-1148 (2007)
Outline of Analytical Method for
N6-HOMe-dAdo in DNA
LC-ESI-MS/MS-SRM Chromatograms of
N6-Me-dAdo in Smokers' Leukocyte DNA
Typical LC-ESI-MS/MS-SRM Chromatograms of
N6-Me-dAdo in Leukocyte DNA
Levels of N6-HOMe-dAdo (as N6-Me-dAdo) in
Leukocyte DNA of Smokers and Non-smokers
Previous Studies of Leukocyte DNA
Adducts in Smokers vs. Non-smokers
• Most used 32P-postlabelling and immunoassay –
inconsistent results comparing smokers and
non-smokers
• Mixed results in 8-OH-dG analyses
• Marginally higher levels of acetaldehyde-DNA
adducts in smokers before stopping
• Significant difference in BPDE-DNA adducts
(2 per 108 vs 1 per 108 nucleotides)
• Our results: 5 per 108 vs. 0.5 per 108 nucleotides
IARC Monographs, Vol 83 (2004); Pavanello et al. Mutat. Res 611: 54 (2006);
Chen et al Chem. Res. Toxicol. 20: 108 (2007)
Sources of Formaldehyde-DNA Adducts
• Formaldehyde itself in cigarette smoke, but
blood levels were not elevated in volunteers
exposed to similar amounts
• Smoking effect on endogenous metabolism
• Released as a metabolite from nicotine, NNK, or
related compounds
• Transfer from formaldehyde-histone adducts
• Secondary metabolite from lipid peroxidation or
inflammation caused by smoking
Conclusions – Formaldehyde DNA
Adducts
• First study to detect formaldehyde-DNA
adducts in humans
• Highly significant differences between
smokers and non-smokers
• Results indicate a previously unrecognized
and potentially important role for
formaldehyde in smoking-induced cancer
M. Wang, G. Cheng, S.S. Hecht et al. Cancer Res., 69: 7170 (2009)
Overall Goal
Elucidate mechanisms of
tobacco-induced cancer and apply this
knowledge to cancer prevention.
We are Making Progress in Tobacco
Control
• Smoke-free legislation
• Increased taxation
• Aggressive anti-tobacco advertising
Age-Adjusted Total U.S. Mortality Rates for
Lung and Bronchus Cancer
100
90
80
60
Both sexes
50
Males
Females
40
30
20
10
Year of Death
Source: SEER data http://seer.cancer.gov/faststats/
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
1981
1980
1979
1978
1977
1976
0
1975
Rate per 100,000
70
Dorothy Hatsukami
Acknowledgements
•
Hecht Lab
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•
Steven Carmella
Mingyao Wang
Irina Stepanov
Pramod Upadhyaya
Brad Hochalter
Silvia Balbo
Shaomei Han
Menglan Chen
Guang Cheng
Lei Meng
Yan Zhong
Aleks Knezevich
John Muzic
Core Facilities
–
–
–
–
–
Pete Villalta
Chap Le
Xianghua Luo
Yan Zhang
Bruce Lindgren
•
Dorothy Hatsukami
– Joni Jensen
– Amanda Anderson
– Rachel Feuer
•
•
•
•
•
Tim Church
Kristin Anderson
Mindy Geisser
Jian-Min Yuan
Mimi Yu
Research Support
• National Cancer Institute
• National Institute of Environmental Health
Sciences
• National Institute on Drug Abuse/NCI/NIAAA
(TTURC)
• American Cancer Society
• Wallin Chair in Cancer Prevention