Smoking and Lung Cancer in China

Hongbing Shen, M.D., Ph.D.Professor of Epidemiology Department of Epidemiology & BiostatisticsNanjing Medical University School of Public HealthTel: 86862747; Email: hbshen@njmu.edu.cn

Smoking & Lung CancerSmoking & Lung Cancer

Richard Doll & Austin B HillRichard Doll & Austin B Hill

Smoking and Carcinoma Smoking and Carcinoma of the Lung. BMJ, 1950of the Lung. BMJ, 1950

Sir Richard Doll: The Godfather of Epidemiology

Richard Doll

Sir Austin B. Hill: The Father of Modern Epidemiology

Austin B. Hill

The case-control study of smoking and lung cancer

The British Doctor Study

What should I Talk?

1 The prevalence of smoking in Chinese in the new century;

2 The trend of lung cancer incidence and histologic types in China;

3 Risk estimates of smoking and lung cancer in Chinese;

4 Smoking - gene interaction in lung cancer

The prevalence of smoking in China

Of China’s population of 1.2 billion people, more than 300 million men and 20 million women are smokers, making China the world’s largest actual and potential national market for cigarettes.

At current smoking rates, by the year 2025, 2 million smoking-related deaths are predicted to occur in China, and at least 50 million Chinese smokers alive today are expected to die prematurely.

Zhang et al. Respiratory 2003

Total cigarette Consumption in China, 1970–2005

Findings of the 1996 National Prevalence Survey

The prevalence rate for ever-smokers in ChinaMen: 66.9%Women: 4.2%Overall prevalence : 37.6% for those > 15 years and older

There were 0.32 billion smokers (age>15 years) in China; 0.3 billion men and 0.02 billion women.

Compared with 1984, the average age for starting smoking in 1996 has reduced from 22.4 years to 19.7 years. The average daily cigarette consumption by men has increased from 13 to 15 cigarettes.

Yang et al. JAMA 1999

The continuous, rapid increase in the number of Chinese smokers is largely due to teenagers taking up smoking. Among teenagers aged 15–19, 18% of men and 0.28% of women were smokers, and more than 18 million had tried smoking.

The prevalence of passive smoking is very high among non-smokers at 53.5%, about 0.3 billion people aged above 15 were affected, with 71.2% at home, especially women and children being exposed.

Yang et al. JAMA 1999

Findings of the 1996 National Prevalence Survey

Prevalence Rate of Current and Former Smoking in Men and Women by age

Yang et al. JAMA 1999

6.9 %60.2 %2001

35-74

Gu et al. Am J Public Health 2004

10.6 %

Environmental tobacco smoke (EST) in non-smokers,2000-2001

Gu et al. Am J Public Health. 2004

MaleMale

Female Female

A cross-sectional survey of smoking in Changzhou, Jiangsu province（2004-2005）

Subjects:A cohort study for chronic diseases in Changzhou city, eligible subjects (20734) aged 25-75 were recruited including 21 villages of suburb of Changzhou, Jiangsu province.

Methods:A cross-sectional survey was conducted in 2004–2005. Information on cigarette smoking was obtained.

Prevalence of Smoking in a Rural Area of South Jiangsu Province, China (2004-2005)

Male Female Total

No Smk Rate*（%）

No Smk Rate*（%）

No Smk Rate*（%）

< 30 606 45.7 856 0.5 1462 19.4

30～ 1530 70.8 2388 0.4 3918 28.4

40～ 2176 75.4 2865 0.7 5041 33.4

50～ 2405 73.6 3050 1.0 5455 33.5

60～ 1302 64.9 1611 0.7 2913 29.8

70～ 762 51.8 1183 2.5 1945 22.7

Total 8781 68.4 11953 1.7 20734 30.0

Age

* Including former smokers Unpublished data

The age-standardized incidence rate (per 100,000) for lung cancer were 43.0 among male, 19.1 among women in 2000 and will be 49.0 among male, 22.9 among women in 2005.

An additional 120,000 new lung cancer cases will occur between 2000 and 2005 (from 0.38 to 0.50 million cases), and the total number of lung cancer cases will increase 26.9% in men and 38.4% in women.

Yang et al, CEBP, 2005

The Epidemic of Lung Cancer in China

1987–1999 age-standardized mortality of Lung Cancer in China

Yang et al. Int J Cancer 2003

Rural

Urban

Male Female

美国1930-2000男性癌症死亡率趋势

肺癌

胃癌

肠癌前列腺癌

美国1930-2000女性癌症死亡率趋势

肺癌

胃癌 肠癌

乳腺癌

子宫癌

Devesa SS et al., IJC 2005

Subjects: The cases were patients with histopathologically confirmed primary lung cancer who were diagnosed and recruited between 1996 and 2005 at Nanjing chest hospital of Jiangsu province.

Totally 1128 lung cancer cases

A Survey on the Characteristics of Lung Cancer Cases from 1996 to 2005

Male : Female Proportions of Lung Cancer Cases from 1996-2005

1996-2000 2001-2005 Total

N N

795

333

1128

383

205

588

N % % %

Male 412 76.3

23.7

100.0

65.1 70.5

Female 128 34.9 29.5

Total 540 100.0 100.0

Gender

1996-2000 2001-2005 Total

N N<30 0 0 3 0.5

6.119.0

3 0.341

16227537525022

1128

3611215616910012588

N

550

11920615010

540

Age Group % % %

31-40 0.9 3.641-50 9.3 14.451-60 22.0 26.5 24.461-70 38.1 28.7 33.271-80 27.8 17.0 22.2>80 1.9 2.0 1.9

Total 100.0 100.0 100.0

Changes of Age Distributions of Lung Cancer Cases from 1996 to 2005

Trends of Average Age of Onset of Lung Cancer Cases

Histological types 1996-2000 2001-2005

Squamous cell 69.51 66.66

Adenocarcinomas 60.90 55.24

Squam-Adenocarcinomas 59.02 55.71

Small cell 61.47 56.06

Total 64.32 58.92

Years

AgeMaleFemale

Histological Types1996-2000

N %2001-2005

N %TotalN %

Squamous cell 219 40.6 181 30.8 400 35.5

Adenocarcinomas 175 32.4 266 45.2 441 39.1

Squam-Adenocarcinomas 50 9.3 55 9.4 105 9.3

Small cell 96 17.7 86 14.6 182 16.1

Total 540 100.0 588 100.0 1128 100.0

Trends of Histological Types in Lung Cancer Cases

Devesa SS et al., IJC 2005

Devesa SS et al., IJC 2005

Risk Estimates between Smoking and Lung Cancer in Chinese

Liu JL et al, BMJ 1998

Ratio of Lung Cancer Mortality between Smokers and Non-smokers

Liu JL et al, BMJ 1998

CancerCancer

ExposureExposure

Cancer-freeCancer-free

CR by 74 yrsM: 5.7%F: 2.6%

(Yang et al, CEBP, 2005)

Genetic susceptibility ?

Research Question: Why only <20% smokers develop lung cancer?

olecular Epidemiology

CancerCancer

Traditional Epidemiology

ExposureExposure ？

(Molecular Epidemiology)

CYP gene family

GST gene family

The multi-step carcinogenic process

Nicotine Nicotine DependentDependent

CarcinogensCarcinogensActivationActivation

DNA DNA DamageDamage

Genetic Genetic mutationmutation

CancerCancer

DNA DNA repairrepair

ApoptosisApoptosis

CYP2A6

CYP2D6

Cell Cycle Control

Molecular Epidemiology of Smoking and Lung Cancer

Exposure Markers

Phenotypes (e.g. DNA adducts)

LOH, methylation, and mutation

Polymorphisms of candidate genes

Gene-environment interactions

DNA repair gene XPC genotypes / haplotypesand risk of lung cancer:A case-control study in a Chinese population

Case-control study of 320 lung cancer cases and 322 cancer-free controls

Examples

Hu Z, …… Shen H. Int J Cancer 2005; 115(3):478-83

nsSNPs in XPC and Lung Cancer Risk

Genotype Cases (n=320) Controls (n=322) Adjusted OR (95%CI)

XPC Ala499Val No. (%) No. (%)CC 124 (38.8) 158 (49.1) 1.0CT 171 (53.4) 145 (45.0) 1.61(1.14-2.27)TT 25 (7.8) 19 (5.9) 1.32(0.67-2.62)

CT+TT 196 (61.2) 164 (50.9) 1.57(1.13-2.19)

XPC Lys939GlnAA 126 (39.4) 141 (43.8) 1.0AC 154 (48.1) 152 (47.2) 1.20(0.85-1.70)CC 40 (12.5) 29 (9.0) 1.28(0.72-2.28)

AC+CC 194 (60.6) 181 (56.2) 1.21(0.87-1.69)

Ala499Val and Lys939Gln combinations

499CC and 939AA 28 (8.8) 51 (15.8) 1.0

Either one variant genotype (499CT/TT or 939AC/CC) 194 (60.6) 197 (61.2) 1.56(0.93-2.63)

Both variant genotypes(499CT/TT and 939AC/CC) 98 (30.6) 74 (23.0) 2.37(1.33-4.21)

XPC codon499 and codon939

Smokingstatus 499CC and

939AAEither one variant genotype(499CT/TT or 939AC/CC)

Both variant genotypes(499CT/TT and

939AC/CC)

Never(Case/Control)

1.00(13/34)

1.61 (0.80-3.24)(83/136)

2.63 (1.23-5.62)(47/51)

Ever(Case/Control)

3.05 (1.15-8.10)(15/17)

5.94 (2.83-12.5)(111/61)

7.36 (3.19-17.00)(51/23)

Joint effect of XPC genotypes and smoking on lung cancer risk

A novel promoter polymorphism (T-77C) of DNA repair gene XRCC1 is associated with risk of lung cancer

Hu Z, …… Shen H. Pharmacogenetics & Genomics 2005 15(7): 457-64.

Case-control study of 710 lung cancer cases and 710 cancer-free controls

XRCC1 T-77C polymorphism and lung cancer risk

Cases(710) Controls(710)

No % No %

XRCC1 T-77C

TT (ref.) 500 70.4 558 78.6 1.00

CT 198 27.9 148 20.9 1.51 (1.17-1.94)

CC 12 1.7 4 0.6 2.98 (0.93-9.59)

CT/CC 210 29.6 152 21.4 1.55 (1.21-1.98)

C allele 222 15.6 156 11.0 P = 0.0003

AdjustedOR (95%CI)

XRCC1 Genotype

11.55

2.663.28

4.07

9.82

0123456789

10

0 1--30 >30 Pack-years of smoking

-77TT

-77CT/CC

XRCC1 T-77C and cumulative smoking

Adj

ust e

d O

R

EXON 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

XRCC1

5’UTR

ATG 3’UTR

-77T>C Exon6 Arg194Trp Exon10 Arg399Gln

+1 -77T

XRCC1 promoter

-1152 +93

Luciferase

XRCC1 promoter

-1152 +93

LuciferasepGL3

-77C

pGL3p77T

p77C

KpnI NheI

Chromosome: 19q13.2

1246-bp

57–64%

This funding was validated by a population from North China

Hao et al. Oncogene 2006

Genetic variants in MGMT and risk of primary lung cancer in Southeastern Chinese: a haplotype based analysis

Case-control study of 500 lung cancer cases and 517 cancer-free controls

Hu Z, … Shen H. Hum Mutat 2007 May;28(5):431-40.

We genotyped 39 SNPs across MGMT based on:HapMap block region coverage MAFFunctional relevance

We use 25 informative SNPs to rebuilt LD blocks

We selected a minimum set of htSNPs within each block to ensure a Rh

2 of at least 0.80 to capture all possible haplotypes that had a frequency of at least 5%.

Haplotype block - based tagSNPs selection

4 14 7 1 1 3 1 1 1 3 1 1 1

SNPs :

MGMT gene structure and haplotype block for Beijing Han Chinese from HapMap

MGMT Tagging SNPs based on the gene blocks(by Haploview program )

25 informative SNPs in 517 controls

10 htSNPs from the 6 blocks

1 1 2 2 2 2htSNPs

MDR Models of selected gene regions and co-variables

Best models CVC *Avg. Testing

Accuracy

Sign Test P Value

One Factor:Pack-years of smoking 100/100 0.5827 0.0009 0.0330

Two Factors:Pack-years of smoking; block 3 99/100 0.5992 0.0018 0.0344

Three Factors:Pack-years of smoking; block 5; rs1625649 100/100 0.6145 0.0000 0.0453

Four Factors:Pack-years of smoking; block 3; block 5; rs1625649 100/100 0.6374 0.0000 0.0146

Five Factors:Pack-years of smoking; block 3; block 5; block 6;

rs162564968/100 0.5349 0.5398 0.3194

* CVC: cross-validation consistency

Conclusions

1 The prevalence of smoking is still high in Chinese in the new century;

2 The incidence and mortality of lung cancer is increasing and the histologic types is changing in China;

3 RR=2-3 for smoking and lung cancer in Chinese;

4 Genetic polymorphisms may play a role in smoking - related lung cancer