indoor air pollution, gene polymorphism and the risk of lung cancer in taiyuan, china lina mu school...
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Indoor Air Pollution, Gene Polymorphism and the Risk of Lung Cancer in Taiyuan, China
Lina MuLina Mu
School of Public Health, Fudan University, ChinaAACR scholar, EPH School of Medicine, Yale University
!! Chinese Female vs US female
Chinese Male vs US Male
Smoking rate and lung cancer incidence
not parallel
Tobacco smoking is considered the most important risk factor for lung cancer
63%
27%
3.8%
22.6%
WHY?
Reasons:
• Chinese female has special environment exposure?• Air Pollution: Indoor?• Lifestyle?• Migrant Study:
Chinese vs Japanese
White
Hawaiian
Lung cancer risk is still high!!!
• • Chinese may be genetically different from US population in resp
onse to tobacco smoking and other environmental exposures?
Chinese population: North vs South
• Role of cigarette smoking in lung cancer risk?
• Role of indoor air pollution in lung cancer risk?
• Role of gene polymorphism in lung cancer risk?
• The etiological heterogeneity between two areas;
Material and Methods
• A case-control study
• Taiyuan City, Shanxi Province: “ Coal town”
--- Major Industry: Coal, steel and Chemistry
--- Outdoor air pollution: Highest TSP in the world, 1997- World Bank
SO2: 10 times WHO guidance value
--- Most frequent coal using area:
--- No related study in recent years around this area
Dafeng City, Jiang Su province
---Much less industry;
---Less outdoor air pollution;
---Different life style;
---less coal using;
Taiyuan Project
• Cases: 399 Newly diagnosed patients with lung cancer from major cancer hospitals in this city between 2005-2006;
• Control: 512 Healthy control from same source population;
• Epidemiological data were collected by in-person interview using a standard questionnaire;
• Data analysis: adjustment: Age, gender, education, income, BMI and pack-year
Distribution of Leading Causes of Cancer Death in Taiyuan City, 2005
Percentage(%)0 5 10 15 20 25 30 35 40
Leukemia
Breast
Brain and other NervousSystem
Pancreas
Colon & Rectum
Esophagus
Liver
Stomach
Lung
MaleFemale
Results-1
Smoking---Lung cancer
>100 case-control
37 cohort studies:
OR: 15-30
-A.J. Sasco 2004
63%
13%
15%
9%
02468101214161820
No <2020-40>40 No <2020-40>40 No <2020-40>40
ADC
SCC
SCLC
Pack-Year
OR
ADCSCCSCLC
Smoking and Risk of Lung Cancer With Different Histotype
Histology Type Male Female Total
Adenocarcinoma 43 (21.4%) 64 (32.5%) 107(26.9%)
Squamous Cell Carcinoma 66(32.8%) 25(12.7%) 91(22.9%)
Small Cell Carcinoma 26(12.9) 31(15.7%) 57(14.3%)
Others 66(32.8) 77(39.1%) 143(35.9%)
• Smoking is still an very important risk factors in this population;
• However it might be less contribution to risk of lung cancer among Chinese female.
Smoking and Risk of Lung Cancer
Indoor Air Pollution
Joint effect of active and passive smoking on lung cancer
Active/ Passive
Cases Controls
Total
Crude OR Adjusted OR
NonePassive onlyActive onlyActive+passiveTotal
41(10)138(35
)25(6)195(49
)399
97(19)225(44)37(7)153(30)512
13836362348911
11.45(0.95-2.21)1.60(0.86-2.99)3.01(1.98-4.60)
11.45(0.93-2.26)3.28(1.55-6.97)5.36(3.08-9.32)
0123456789
10
A-,P- A-,P+
A+,P- A+,P+
Smoking
Status
OR
Passive Smoking
Coal Using for Cooking?
Coal using for Heating?
Ventilation using in Kitchen?
Coal using for cooking or heating and risk of lung cancer, Chinese Female
0
2
4
6
8
10
12
14
16
18
NJ1 SY1 SY2 GS TW HB GZ SH
OR
REVIEW
Kleinerman R 2002
► Non-smoking Chinese female: OR for Coal using: 1.42, sig
---Zhang Y 2001
0
2
4
6
8
10
12
14
16
18
SCC CSt Cbu F/M SCC ADC All G(M) F/M F/M
NJ2 SY HB FZ GZ XW GS
OR
Gas vs Coal
Coal using for cooking or heating and Lung cancer risk, Chinese Male (&female)
0
0.5
1
1.5
2
2.5
3
3.5
Elec/Gas Coal/Wood Elec/Gas Coal/Wood
None-smoker Smoker
OR
Male Female
0.1
1
10
100
Elec/Gas Coal/Wood Elec/Gas Coal/Wood
OR
Cooking fuel (Coal) and risk of lung Cancer?
Cooking fuel and risk of lung Cancer?
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Elec/Gas Coal/Wood
ADC SCC Other
OR
Elec/Gas Coal/Wood
Elec/Gas Coal/Wood
0
1
2
3
4
5
6El
c/Ga
s
Coal/Wood
Elc/
Gas
Coal/Wood
Elec
/Gas
Coal/Wood
Elec
/Gas
Coal/Wood
Elec
/Gas
Coal/Wood
Elec
/Gas
Coal/Wood
Elec
/Gas
Coal/Wood
None
smoker
Smoker
ADC SCC Other Male
Female
O R
Coal Using for Heating and risk of lung Cancer?
Ventilation in the kitchen and Risk of Lung Cancer
0
1
2
3
4
5
6
None smoker Smok
erADC
SCC
Other
Male
Female
OR
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
About 40%, 30% patients have the history of using coal as cooking fuel or heating materials, and 50% patients didn’t use ventilation in Kitchen in the study area.
Indoor coal using exposure has much stronger asso
ciation with lung cancer in female or none-smoker;
The association is more obviously between coal using indoor air pollution and adenocarcinoma;
Indoor Air Pollution and Lung Cancer
Indoor Air Pollution and Risk Lung Cancer
●The smoke generated from incomplete combustion of these fuels contains constituents that have been identified as known or suspected carcinogens:
PAHs: well known carcinogen from coal smoke;
Benzo(a)pyrene:
from unvented soft, smoky coal used
for cooking and heating; Coal using in room=20 cigarette/day (Shanghai)
Particles:
●Because of the cold weather, many windy days and outdoor air pollution in winter in North China, most family don’t open the window for a long time, maybe for the whole winter. Without Ventilation equipment, harmful compound generated from cooking and heating will accumulated and cause the increased risk of Lung cancer.
Exogenous carcinogens
Tobacco consumption
Occupational Exposures
OutdoorAir pollution
Indoor exposure
PAHs Xenobiotics
AreneAlkine,
etc
Active carcinogens
CYP1A1 Detoxified
carcinogens
GSTT1
NQO1
GSTM1
not repaired
G
S
G2
M
DNA damage repaired
Normal cell
DNA Repair Gene
Cell cycle
Programmed cell
death
Oncogene Activate
Tumor suppress / repair Gene --Silenced
Hypo-methylation
Hyper-methylation
Carcinogenesis
DNA Damage
Lung cancer
NQO1
Polymorphic metabolizing genes associated with lung cancer
Polymorphic Human Enzyme System
Typical Substrate Carcinogens or Substrate
P450 Mono-oxygenases
CYP1A1
Benzo[a]pyrene PAHs
Oxido-Reductases
NQO1
Diaziquone Quinoids
CYP1A1Case Control
OR(95%CI) aOR(95%CI)N (%) N (%)
M1/M1184(46.46
)214(41.96) 1.00
1.00
M1/M2170(42.93
)244(47.84) 0.81(0.61-1.07)
0.79(0.58-1.07)
M2/M2 42(10.61) 52(10.20) 0.94(0.60-1.48) 0.87(0.53-1.40)
AOR for Adenocarcinoma: 1.13, 0.90
AOR For Squamous Cell Carcinoma: 0.54, 1.65
CYP1A1 and Lung Cancer
No interaction between CYP1A1 and smoking with the risk of lung cancer
NQO1
• NQO1 is involved in both metabolic activation and detoxification of carcinogens;
---Prevent the formation of BP quinone-DNA adduct;
---Metabolically active carcinogenic heterocyclic amines present in smoke;
NQO1 and Lung Cancer
NQO1
Case Control
OR(95%CI) AOR(95%CI)N (%) N (%)
Pro/Pro 133(33.9) 196(41.3) 1.00 1.00
Pro/Ser 155(39.5) 165(34.7)1.38(1.02-
1.89)1.48(1.06-2.08)
Ser/Ser 104(26.5) 114(24.0)1.34(0.95-
1.90)1.41(0.97-2.05)
pro/pro pro/ser ser/ser Any ser
ORADC 1.00 1.51(0.90-2.55) 1.57(0.90-2.76) 1.54(0.96-2.45)
ORSCC 1.00 1.44(0.82-2.55) 0.57(0.27-1.20) 1.05(0.62-1.77)
Ser Allele(41.4%) is similar with that reported in Chinese population
NQO1, Indoor Air Pollution and Lung Cancer
Number of exposure to indoor Air pollution factors
0
2
4
6
8
10
12
pro/proAny ser0 1 2 3
OR
pro/proAny serpro/proAny serpro/proAny ser
No interaction between NQO1 and smoking with the risk of lung cancer
DNA repair
Friedberg, Nature Reviews Cancer 2001; 1: 22-33
Od
ds
Rat
ioDRC (%) by Quartile
Risk of Risk of LungLung Cancer Cancer
Associated with Low DRCAssociated with Low DRC
High Low
In Vitro Adduct Assay (genomic DNA)
Trend test : P < 0.001
Li et al, Cancer Res., 2001
0
1
2
3
4
5
6
Ist 2nd 3rd 4th
Human DNA Repair PathwaysHuman DNA Repair Pathways
Gene Type Damage
XRCC1 Base excision repairBase excision repair Single base damage repair
LIG1 Nucleotide excision repair Bulky nucleotide damage including UV photoproducts and chemical carcinogen-induced adducts
Mismatch repair Base mismatch
Recombinational repair Double strand breaks V(D)J recombination
DNA Repair
• XRCC1: Base excision repairXRCC1: Base excision repair Required for the efficient repair of single-strand Required for the efficient repair of single-strand
breaks and damaged bases in DNA;breaks and damaged bases in DNA;
Its absence leads to a substantial reduction in tIts absence leads to a substantial reduction in the levels of its partner ligase III;he levels of its partner ligase III;
Of 60 SNPs in this gene, Arg194Trp on exon 6, AOf 60 SNPs in this gene, Arg194Trp on exon 6, A
rg399Gln on exon 10 are extensively studied.rg399Gln on exon 10 are extensively studied.
XRCC1 condon194 Polymorphism and Lung cancer
XRCC1
Case Control
OR(95%CI) AOR(95%CI)N (%) N (%)
Arg/Arg 164(49.9) 282(62.8) 1.00 1.00
Arg/Trp 113(34.4) 116(25.8) 1.68(1.21-2.31) 1.90(1.33-2.72)
Trp/Trp 52(15.8) 51(11.4) 1.75(1.14-2.70) 1.96(1.21-3.16)
Any Trp 165(50.2) 167(37.2) 1.70(1.27-2.27) 1.81(1.32-2.48)
No difference over histotype
Hung RJ American Journal of Epidemiology, 2005
25.8%, 11.4%
Smoking, XRCC1 194 and Lung cancer
00.51
1.52
2.53
3.54
4.55
OR
S-,Arg/Arg
S-,Arg/Trp
S-,Trp/Trp
S+,Arg/Arg
S+,Arg/Trp
S+,Trp/Trp
Indoor Air Pollution, XRCC1 194 Polymorphism and Lung Cancer
0
5
10
15
20
25
30
0 1 2 3
OR
Arg/Arg Any Trp Arg/Arg Any Trp Arg/ArgAny Trp Arg/Arg Any Trp
XRCC1 condon399 polymorphism and Lung
cancer
Genotype
Case ControlOR(95%CI) AOR(95%CI)
N(%) N(%)
Arg/Arg 161(48.8) 227(47.8) 1.00 1.00
Arg/Gln 119(36.1) 202(42.5) 0.83(0.61-1.13) 0.86(0.62-1.20)
Gln/Gln 50(15.2) 46(9.7) 1.53(0.98-2.40) 1.59(0.97-2.60)
Hung RJ American Journal of Epidemiology, 2005
42.5% 9.7%
Kiyohara C, Lung Cancer,2006
XRCC1 399 and lung cancerMeta-analysis
Kiyohara C, Lung Cancer,2006
Smoking, XRCC1 399 and Lung Cancer
Smoking GenotypeCase Control
Crude OR(95%) AOR(95%CI)N(%) N(%)
No
Arg/Arg 45(13.6) 93(19.6) 1.00 1.00
Arg/Gln 39(11.8) 91(19.2) 0.89(0.53-1.49) 1.06(0.62-1.82)
Gln/Gln 15(4.6) 25(5.3) 1.24(0.60-2.58) 1.50(0.70-3.22)
Yes
Arg/Arg 116(35.2) 134(28.2) 1.79(1.16-2.76) 2.65(1.57-4.46)
Arg/Gln 80(24.2) 111(23.4) 1.49(0.94-2.35) 2.30(1.35-3.92)
Gln/Gln 35(10.6) 21(4.4) 3.44(1.80-6.58) 5.00(2.43-10.30)
00.51
1.52
2.53
3.54
4.55
OR
S-,Arg/Arg
S-,Arg/Gln
S-,Gln/Gln
S+,Arg/Arg
S+,Arg/Gln
S+,Gln/Gln
LIG1 and Lung Cancer
• Nuclear Enzyme;
• Be required for joining Okazaki fragments during DNA replication and sealing single-strand breaks;
• Be involved in both nucleotide excision repair and long-patch base-excision repair;
• Mutations in LIG1 results in hypersensitivity to DNA-damaging agents.
LIG1 and Lung Cancer
Genotype
Case Control
OR(95%CI) AOR(95%CI)N (%) N (%)
A/A 192(48.73) 265(51.86) 1.00 1.00
A/C 181(45.94) 218(42.66) 1.15(0.87-1.50) 1.07(0.80-1.44)
C/C 21(5.33) 28(5.48) 1.04(0.57-1.88) 0.70(0.35-1.42)
No difference over histotype
No interaction between LIG1 and smoking with the risk of lung cancer
Summary
• Increased risk of lung cancer associated with NQO1 polymorphism.
• Polymorphisms in this gene might modify the association between carcinogen in indoor air pollution and lung-cancer risk.
• DNA Repair gene XRCC1 polymorphism might be associated with increased risk of lung cancer;
• XRCC1 might modify the effect of smoking, indoor air pollution and increase the risk of lung cancer;
Summary
Fudan University Shunzhang Yu
Jia Su Jiawei Li
Guorong Wei Chuanwei Chen
Taiyuan CDC Li Liu
Jianping Shi Baoxing Zhao
Acknowledgements
UCLA Zuofeng Zhang Shun-Chun Chuang Yifang Zhu
Shanxi Tumor hospital
Ruigui Niu
XiaoYou Han
Thanks!Thanks!