Smoking and Lung Cancer in China

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1 Smoking and Lung Cancer in China Hongbing Shen, M.D., Ph.D. Professor of Epidemiology Department of Epidemiology & Biostatistics Nanjing Medical University School of Public Health Tel: ;

2 Smoking & Lung Cancer Richard Doll & Austin B Hill Smoking and Carcinoma of the Lung. BMJ, 1950

3 Richard Doll Sir Richard Doll: The Godfather of Epidemiology

4 Austin B. Hill The case-control study of smoking and lung cancer The British Doctor Study Sir Austin B. Hill: The Father of Modern Epidemiology

5 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

6 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

7 Total cigarette Consumption in China,

8 Findings of the 1996 National Prevalence Survey The prevalence rate for ever-smokers in China Men: 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

9 Findings of the 1996 National Prevalence Survey 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 nonsmokers 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

10 Prevalence Rate of Current and Former Smoking in Men and Women by age Yang et al. JAMA % 60.2 % % Gu et al. Am J Public Health 2004

11 Male Environmental tobacco smoke (EST) in nonsmokers, Female Gu et al. Am J Public Health. 2004

12 A cross-sectional survey of smoking in Changzhou, Jiangsu province( ) Subjects: A cohort study for chronic diseases in Changzhou city, eligible subjects (20734) aged were recruited including 21 villages of suburb of Changzhou, Jiangsu province. Methods: A cross-sectional survey was conducted in Information on cigarette smoking was obtained.

13 Prevalence of Smoking in a Rural Area of South Jiangsu Province, China ( ) Age Male Female Total No Smk Rate* (%) No Smk Rate* (%) No Smk Rate* (%) < ~ ~ ~ ~ ~ Total * Including former smokers Unpublished data

14 The Epidemic of Lung Cancer in China 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 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

15 Rural Male Female agestandardized mortality of Lung Cancer in China Yang et al. Int J Cancer 2003 Urban

17 美国男性癌症死亡率趋势肺癌胃癌肠癌前列腺癌

18 美国女性癌症死亡率趋势乳腺癌肺癌胃癌子宫癌肠癌

19 Devesa SS et al., IJC 2005

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

21 Male : Female Proportions of Lung Cancer Cases from Total Gender N % N % N % Male Female Total

22 Changes of Age Distributions of Lung Cancer Cases from 1996 to Total Age Group N % N % N % < > Total

23 Trends of Average Age of Onset of Lung Cancer Cases Age Male Female Years Histological types Squamous cell Adenocarcinomas Squam-Adenocarcinomas Small cell Total

24 Trends of Histological Types in Lung Cancer Cases Histological Types N % N % Total N % Squamous cell Adenocarcinomas Squam-Adenocarcinomas Small cell Total

25 Devesa SS et al., IJC 2005

26 Devesa SS et al., IJC 2005

27 Risk Estimates between Smoking and Lung Cancer in Chinese

28 Liu JL et al, BMJ 1998

29 Ratio of Lung Cancer Mortality between Smokers and Non-smokers Liu JL et al, BMJ 1998

30 Research Question: Why only <20% smokers develop lung cancer? Genetic susceptibility? Cancer CR by 74 yrs M: 5.7% F: 2.6% (Yang et al, CEBP, 2005) Exposure Cancer-free

31 olecular Epidemiology Traditional Epidemiology Exposure? Cancer (Molecular Epidemiology)

32 The multi-step carcinogenic process Nicotine Dependent Carcinogens Activation DNA Damage DNA repair CYP2A6 CYP gene family Cell Cycle Control CYP2D6 GST gene family Genetic mutation Apoptosis Cancer

33 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

34 Examples DNA repair gene XPC genotypes / haplotypes and 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 Hu Z, Shen H. Int J Cancer 2005; 115(3):478-83

35 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) 1.0 CT 171 (53.4) 145 (45.0) 1.61( ) TT 25 (7.8) 19 (5.9) 1.32( ) CT+TT 196 (61.2) 164 (50.9) 1.57( ) XPC Lys939Gln AA 126 (39.4) 141 (43.8) 1.0 AC 154 (48.1) 152 (47.2) 1.20( ) CC 40 (12.5) 29 (9.0) 1.28( ) AC+CC 194 (60.6) 181 (56.2) 1.21( ) Ala499Val and Lys939Gln combinations 499CC and 939AA 28 (8.8) 51 (15.8) 1.0 Either one variant genotype (499CT/TT or 939AC/CC) Both variant genotypes (499CT/TT and 939AC/CC) 194 (60.6) 197 (61.2) 1.56( ) 98 (30.6) 74 (23.0) 2.37( )

36 Joint effect of XPC genotypes and smoking on lung cancer risk XPC codon499 and codon939 Smoking status 499CC and 939AA Either 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 ( ) (83/136) 2.63 ( ) (47/51) Ever (Case/Control) 3.05 ( ) (15/17) 5.94 ( ) (111/61) 7.36 ( ) (51/23)

37 A novel promoter polymorphism (T-77C) of DNA repair gene XRCC1 is associated with risk of lung cancer Case-control study of 710 lung cancer cases and 710 cancer-free controls Hu Z, Shen H. Pharmacogenetics & Genomics (7):

38 XRCC1 T-77C polymorphism and lung cancer risk XRCC1 Genotype XRCC1 T-77C Cases(710) Controls(710) No % No % Adjusted OR (95%CI) TT (ref.) CT ( ) CC ( ) CT/CC ( ) C allele P =

39 XRCC1 T-77C and cumulative smoking Adjusted OR TT -77CT/CC >30 Pack-years of smoking

40 XRCC1 Chromosome: 19q13.2 EXON UTR ATG 3 UTR -77T>C Exon6 Arg194Trp Exon10 Arg399Gln 1246-bp -77T +1 p77t KpnI p77c XRCC1 promoter C XRCC1 promoter Luciferase Luciferase pgl3 pgl3 NheI 57 64%

41 This funding was validated by a population from North China Hao et al. Oncogene 2006

42 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):

43 Haplotype block - based tagsnps selection We genotyped 39 SNPs across MGMT based on: HapMap block region coverage MAF Functional relevance We use 25 informative SNPs to rebuilt LD blocks We selected a minimum set of htsnps within each block to ensure a R h2 of at least 0.80 to capture all possible haplotypes that had a frequency of at least 5%.

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

45 MGMT Tagging SNPs based on the gene blocks (by Haploview program ) htsnps htsnps from the 6 blocks 25 informative SNPs in 517 controls

46 MDR Models of selected gene regions and co-variables Best models CVC * Accurac Avg. Testing y One Factor: Pack-years of smoking Sign Test P Value 100/ Two Factors: Pack-years of smoking; block 3 Three Factors: Pack-years of smoking; block 5; rs Four Factors: Pack-years of smoking; block 3; block 5; rs Five Factors: Pack-years of smoking; block 3; block 5; block 6; rs / / / / * CVC: cross-validation consistency

47 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

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