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!