Lung Cancer in Never Smokers

  • Gabriel Alberto Rivera
  • Heather WakeleeEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 893)


Lung cancer is predominantly associated with cigarette smoking; however, a substantial minority of patients with the disease have never smoked. In the US it is estimated there are 17,000–26,000 annual deaths from lung cancer in never smokers, which as a separate entity would be the seventh leading cause of cancer mortality. Controversy surrounds the question of whether or not the incidence of lung cancer in never-smokers is increasing, with more data to support this observation in Asia. There are several factors associated with an increased risk of developing lung cancer in never smokers including second hand smoke, indoor air pollution, occupational exposures, and genetic susceptibility among others. Adenocarcinoma is the most common histology of lung cancer in never smokers and in comparison to lung cancer in smokers appears less complex with a higher likelihood to have targetable driver mutations.


Non-smoker lung cancer Lung cancer in nonsmokers 


  1. 1.
    Jemal A et al (2008) Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 100(23):1672–1694PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30PubMedCrossRefGoogle Scholar
  3. 3.
    Weiss W (1997) Cigarette smoking and lung cancer trends. A light at the end of the tunnel? Chest 111(5):1414–1416PubMedCrossRefGoogle Scholar
  4. 4.
    Bryant A, Cerfolio RJ (2007) Differences in epidemiology, histology, and survival between cigarette smokers and never-smokers who develop non-small cell lung cancer. Chest 132(1):185–192PubMedCrossRefGoogle Scholar
  5. 5.
    Dutu T et al (2005) Differential expression of biomarkers in lung adenocarcinoma: a comparative study between smokers and never-smokers. Ann Oncol 16(12):1906–1914PubMedCrossRefGoogle Scholar
  6. 6.
    Subramanian J, Govindan R (2007) Lung cancer in never smokers: a review. J Clin Oncol 25(5):561–570PubMedCrossRefGoogle Scholar
  7. 7.
    Sun S, Schiller JH, Gazdar AF (2007) Lung cancer in never smokers–a different disease. Nat Rev Cancer 7(10):778–790PubMedCrossRefGoogle Scholar
  8. 8.
    Okamoto I et al (2006) EGFR mutation in gefitinib-responsive small-cell lung cancer. Ann Oncol 17(6):1028–1029PubMedCrossRefGoogle Scholar
  9. 9.
    Shiao TH et al (2011) Epidermal growth factor receptor mutations in small cell lung cancer: a brief report. J Thorac Oncol 6(1):195–198PubMedCrossRefGoogle Scholar
  10. 10.
    Antony GK et al (2010) Small cell lung cancer in never smokers: report of two cases. J Thorac Oncol 5(5):747–748PubMedCrossRefGoogle Scholar
  11. 11.
    Kurahara Y et al (2012) Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke. Clin Lung Cancer 13(1):75–79PubMedCrossRefGoogle Scholar
  12. 12.
    Samet JM et al (2009) Lung cancer in never smokers: clinical epidemiology and environmental risk factors. Clin Cancer Res 15(18):5626–5645PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Witschi H (2001) A short history of lung cancer. Toxicol Sci 64(1):4–6PubMedCrossRefGoogle Scholar
  14. 14.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase no. 11 [internet]. Available from: Cited 28 Dec 2013
  15. 15.
    (1987) Rates and rate standardization. In: Breslow NE, Day NE (eds) The design and analysis of cohort studies. Oxford University Press, Oxford, p 415Google Scholar
  16. 16.
    Ezzati M et al (2005) Role of smoking in global and regional cancer epidemiology: current patterns and data needs. Int J Cancer 116(6):963–971PubMedCrossRefGoogle Scholar
  17. 17.
    Liu BQ et al (1998) Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths. BMJ 317(7170):1411–1422PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Thun MJ et al (2008) Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies. PLoS Med 5(9):e185PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Siegel R et al (2014) Cancer statistics, 2014. CA Cancer J Clin 64(1):9–29PubMedCrossRefGoogle Scholar
  20. 20.
    Thun MJ et al (2006) Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst 98(10):691–699PubMedCrossRefGoogle Scholar
  21. 21.
    Parkin DM et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedCrossRefGoogle Scholar
  22. 22.
    Wakelee HA et al (2007) Lung cancer incidence in never smokers. J Clin Oncol 25(5):472–478PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Gazdar AF, Thun MJ (2007) Lung cancer, smoke exposure, and sex. J Clin Oncol 25(5):469–471PubMedCrossRefGoogle Scholar
  24. 24.
    Yano T et al (2008) Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer 113(5):1012–1018PubMedCrossRefGoogle Scholar
  25. 25.
    Gomez SL et al (2011) Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and Non-Hispanic white women who have never smoked. Cancer Epidemiol Biomarkers Prev 20(3):545–554PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2004) Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 83:1–1438PubMedCentralGoogle Scholar
  27. 27.
    Vineis P et al (2005) Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study. BMJ 330(7486):277PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Vineis P et al (2004) Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst 96(2):99–106PubMedCrossRefGoogle Scholar
  29. 29.
    Clement-Duchene C et al (2010) Characteristics of never smoker lung cancer including environmental and occupational risk factors. Lung Cancer 67(2):144–150PubMedCrossRefGoogle Scholar
  30. 30.
    Bagley SC, White H, Golomb BA (2001) Logistic regression in the medical literature: standards for use and reporting, with particular attention to one medical domain. J Clin Epidemiol 54(10):979–985PubMedCrossRefGoogle Scholar
  31. 31.
    Brennan P et al (2004) Secondhand smoke exposure in adulthood and risk of lung cancer among never smokers: a pooled analysis of two large studies. Int J Cancer 109(1):125–131PubMedCrossRefGoogle Scholar
  32. 32.
    Brenner DR et al (2010) Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors. BMC Cancer 10:285PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gorlova OY et al (2007) Aggregation of cancer among relatives of never-smoking lung cancer patients. Int J Cancer 121(1):111–118PubMedCrossRefGoogle Scholar
  34. 34.
    Kurahashi N et al (2008) Passive smoking and lung cancer in Japanese non-smoking women: a prospective study. Int J Cancer 122(3):653–657PubMedCrossRefGoogle Scholar
  35. 35.
    Nyberg F et al (1998) A European validation study of smoking and environmental tobacco smoke exposure in nonsmoking lung cancer cases and controls. Cancer Causes Control 9(2):173–182PubMedCrossRefGoogle Scholar
  36. 36.
    Wells AJ et al (1998) Misclassification rates for current smokers misclassified as nonsmokers. Am J Public Health 88(10):1503–1509PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Asomaning K et al (2008) Second hand smoke, age of exposure and lung cancer risk. Lung Cancer 61(1):13–20PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Lissowska J et al (2005) Lung cancer and indoor pollution from heating and cooking with solid fuels: the IARC international multicentre case-control study in Eastern/Central Europe and the United Kingdom. Am J Epidemiol 162(4):326–333PubMedCrossRefGoogle Scholar
  39. 39.
    Samet JM (1989) Radon and lung cancer. J Natl Cancer Inst 81(10):745–757PubMedCrossRefGoogle Scholar
  40. 40.
    Krewski D et al (2006) A combined analysis of North American case-control studies of residential radon and lung cancer. J Toxicol Environ Health A 69(7):533–597PubMedCrossRefGoogle Scholar
  41. 41.
    (1980) Fundamental measures of disease occurrence and association. In: Breslow NE, Day NE (eds) The analysis of case-control studies. International Agency for Research on Cancer, LyonGoogle Scholar
  42. 42.
    Sandler DP et al (2006) Indoor radon and lung cancer risk in Connecticut and Utah. J Toxicol Environ Health A 69(7):633–654PubMedCrossRefGoogle Scholar
  43. 43.
    Darby S et al (2005) Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. BMJ 330(7485):223PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Leuraud K et al (2011) Radon, smoking and lung cancer risk: results of a joint analysis of three European case-control studies among uranium miners. Radiat Res 176(3):375–387PubMedCrossRefGoogle Scholar
  45. 45.
    Bonner MR et al (2006) Radon, secondhand smoke, glutathione-S-transferase M1 and lung cancer among women. Int J Cancer 119(6):1462–1467PubMedCrossRefGoogle Scholar
  46. 46.
    Zhang J, Smith KR (2003) Indoor air pollution: a global health concern. Br Med Bull 68:209–225PubMedCrossRefGoogle Scholar
  47. 47.
    Hosgood HD 3rd et al (2010) In-home coal and wood use and lung cancer risk: a pooled analysis of the International Lung Cancer Consortium. Environ Health Perspect 118(12):1743–1747PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Bonjour S et al (2013) Solid fuel use for household cooking: country and regional estimates for 1980–2010. Environ Health Perspect 121(7):784–790PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kleinerman RA et al (2002) Lung cancer and indoor exposure to coal and biomass in rural China. J Occup Environ Med 44(4):338–344PubMedCrossRefGoogle Scholar
  50. 50.
    Barone-Adesi F et al (2012) Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study. BMJ 345:e5414PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Hosgood HD 3rd et al (2011) Household coal use and lung cancer: systematic review and meta-analysis of case-control studies, with an emphasis on geographic variation. Int J Epidemiol 40(3):719–728PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lan Q et al (2002) Household stove improvement and risk of lung cancer in Xuanwei, China. J Natl Cancer Inst 94(11):826–835PubMedCrossRefGoogle Scholar
  53. 53.
    Gorlova OY et al (2006) Never smokers and lung cancer risk: a case-control study of epidemiological factors. Int J Cancer 118(7):1798–1804PubMedCrossRefGoogle Scholar
  54. 54.
    van Loon AJ et al (1997) Occupational exposure to carcinogens and risk of lung cancer: results from The Netherlands cohort study. Occup Environ Med 54(11):817–824PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Zheng W et al (1987) Lung cancer and prior tuberculosis infection in Shanghai. Br J Cancer 56(4):501–504PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Hinds MW, Cohen HI, Kolonel LN (1982) Tuberculosis and lung cancer risk in nonsmoking women. Am Rev Respir Dis 125(6):776–778PubMedGoogle Scholar
  57. 57.
    Daniels CE, Jett JR (2005) Does interstitial lung disease predispose to lung cancer? Curr Opin Pulm Med 11(5):431–437PubMedCrossRefGoogle Scholar
  58. 58.
    Hubbard R et al (2000) Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med 161(1):5–8PubMedCrossRefGoogle Scholar
  59. 59.
    Le Jeune I et al (2007) The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med 101(12):2534–2540PubMedCrossRefGoogle Scholar
  60. 60.
    Wells C, Mannino DM (1996) Pulmonary fibrosis and lung cancer in the United States: analysis of the multiple cause of death mortality data, 1979 through 1991. South Med J 89(5):505–510PubMedCrossRefGoogle Scholar
  61. 61.
    Prochazka M et al (2005) Ionizing radiation and tobacco use increases the risk of a subsequent lung carcinoma in women with breast cancer: case-only design. J Clin Oncol 23(30):7467–7474PubMedCrossRefGoogle Scholar
  62. 62.
    Travis LB et al (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 94(3):182–192PubMedCrossRefGoogle Scholar
  63. 63.
    van Leeuwen FE et al (1995) Roles of radiotherapy and smoking in lung cancer following Hodgkin’s disease. J Natl Cancer Inst 87(20):1530–1537PubMedCrossRefGoogle Scholar
  64. 64.
    Dacic S et al (2014) RET rearrangements in lung adenocarcinoma and radiation. J Thorac Oncol 9(1):118–120PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Nitadori J et al (2006) Association between lung cancer incidence and family history of lung cancer: data from a large-scale population-based cohort study, the JPHC study. Chest 130(4):968–975PubMedCrossRefGoogle Scholar
  66. 66.
    Gao Y et al (2009) Family history of cancer and nonmalignant lung diseases as risk factors for lung cancer. Int J Cancer 125(1):146–152PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Wu PF et al (2004) Cancer aggregation and complex segregation analysis of families with female non-smoking lung cancer probands in Taiwan. Eur J Cancer 40(2):260–266PubMedCrossRefGoogle Scholar
  68. 68.
    Bell DW et al (2005) Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 37(12):1315–1316PubMedCrossRefGoogle Scholar
  69. 69.
    Ohtsuka K et al (2011) Familial lung adenocarcinoma caused by the EGFR V843I germ-line mutation. J Clin Oncol 29(8):e191–e192PubMedCrossRefGoogle Scholar
  70. 70.
    Yamamoto H et al (2014) Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J Natl Cancer Inst 106(1):djt338PubMedCrossRefGoogle Scholar
  71. 71.
    Sanchez-Cespedes M et al (2001) Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers. Cancer Res 61(4):1309–1313PubMedGoogle Scholar
  72. 72.
    Wong MP et al (2003) Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers. Cancer 97(5):1263–1270PubMedCrossRefGoogle Scholar
  73. 73.
    Hsiung CA, et al (2010) The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia. PLoS Genet 6(8)Google Scholar
  74. 74.
    Wang Y et al (2010) Role of 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers. Carcinogenesis 31(2):234–238PubMedCrossRefGoogle Scholar
  75. 75.
    Wang Y et al (2008) Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet 40(12):1407–1409PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Amos CI et al (2010) A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokers. Cancer Res 70(6):2359–2367PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Truong T et al (2010) Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst 102(13):959–971PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Li Y et al (2010) Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet Oncol 11(4):321–330PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ahn MJ et al (2012) The 18p11.22 locus is associated with never smoker non-small cell lung cancer susceptibility in Korean populations. Hum Genet 131(3):365–372PubMedCrossRefGoogle Scholar
  80. 80.
    Lan Q et al (2012) Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet 44(12):1330–1335PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Hosgood HD 3rd et al (2012) Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia. Hum Genet 131(7):1197–1203PubMedCrossRefGoogle Scholar
  82. 82.
    Miki D et al (2010) Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat Genet 42(10):893–896PubMedCrossRefGoogle Scholar
  83. 83.
    Shiraishi K et al (2012) A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat Genet 44(8):900–903PubMedCrossRefGoogle Scholar
  84. 84.
    Raimondi S et al (2005) Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study. Mutat Res 592(1–2):45–57PubMedCrossRefGoogle Scholar
  85. 85.
    Taioli E et al (2003) Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years. Int J Epidemiol 32(1):60–63PubMedCrossRefGoogle Scholar
  86. 86.
    Wenzlaff AS et al (2005) CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study. Carcinogenesis 26(12):2207–2212PubMedCrossRefGoogle Scholar
  87. 87.
    Gorlova OY et al (2008) DNA repair capacity and lung cancer risk in never smokers. Cancer Epidemiol Biomarkers Prev 17(6):1322–1328PubMedCrossRefGoogle Scholar
  88. 88.
    Lo YL et al (2010) ATM polymorphisms and risk of lung cancer among never smokers. Lung Cancer 69(2):148–154PubMedCrossRefGoogle Scholar
  89. 89.
    Jung CY et al (2006) Polymorphisms in the hMSH2 gene and the risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev 15(4):762–768PubMedCrossRefGoogle Scholar
  90. 90.
    Lo YL et al (2011) Polymorphisms of MLH1 and MSH2 genes and the risk of lung cancer among never smokers. Lung Cancer 72(3):280–286PubMedCrossRefGoogle Scholar
  91. 91.
    Govindan R et al (2012) Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150(6):1121–1134PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Kawaguchi T et al (2010) Gender, histology, and time of diagnosis are important factors for prognosis: analysis of 1499 never-smokers with advanced non-small cell lung cancer in Japan. J Thorac Oncol 5(7):1011–1017PubMedCrossRefGoogle Scholar
  93. 93.
    Toh CK et al (2006) Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol 24(15):2245–2251PubMedCrossRefGoogle Scholar
  94. 94.
    Zhang Y et al (2012) Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res 18(7):1947–1953PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Chougule A et al et al (2013) Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity. PLoS One 8(10)Google Scholar
  96. 96.
    Subramanian J, Govindan R (2008) Molecular genetics of lung cancer in people who have never smoked. Lancet Oncol 9(7):676–682PubMedCrossRefGoogle Scholar
  97. 97.
    Dacic S (2013) Molecular genetic testing for lung adenocarcinomas: a practical approach to clinically relevant mutations and translocations. J Clin Pathol 66(10):870–874PubMedCrossRefGoogle Scholar
  98. 98.
    Mazieres J et al (2013) Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 31(16):1997–2003PubMedCrossRefGoogle Scholar
  99. 99.
    Kwak EL et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Bergethon K et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30(8):863–870PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Shaw AT et al (2011) Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12(11):1004–1012PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Suehara Y et al (2012) Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. Clin Cancer Res 18(24):6599–6608PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Wang R et al (2012) RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol 30(35):4352–4359PubMedCrossRefGoogle Scholar
  104. 104.
    Subramanian J et al (2007) Presentation and stage-specific outcomes of lifelong never-smokers with non-small cell lung cancer (NSCLC). J Thorac Oncol 2(9):827–830PubMedCrossRefGoogle Scholar
  105. 105.
    Nordquist LT et al (2004) Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest 126(2):347–351PubMedCrossRefGoogle Scholar
  106. 106.
    Kawaguchi T et al (2010) Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases. J Thorac Oncol 5(7):1001–1010PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Stanford UniversityStanfordUSA

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