<Hypothesis> 비흡연여성의폐암발생과관련한교정가능위험요인 Modifiable Risk Factors of Lung cancer in Never-Smoker Women 1

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1 <Hypothesis> 비흡연여성의폐암발생과관련한교정가능위험요인 Modifiable Risk Factors of Lung cancer in Never-Smoker Women 배종면 Jong-Myon Bae 제주대학교의학전문대학원예방의학교실 Department of Preventive Medicine, Jeju National University School of Medicine 교신저자 : 배종면 jmbae@jejunu.ac.kr Running title: Lung Cancer in Never-Smoker Women 1

2 <Hypothesis> 비흡연여성의폐암발생과관련한교정가능위험요인 Modifiable Risk Factors of Lung cancer in Never-Smoker Women 1

3 Abstract Women with never-smoking history and adenocarcinoma showed a increasing trend in lung cancer occurrence in Koreans during The modifiable factors of neversmoker lung cancer (NSLCa) in women would be hormone and oncogenic virus infection. Based on previous studies, hormone replacement therapy (HRT) and human papillomavirus (HPV) infection might have protective and risk effect, respectively. It is necessary that a pooled analysis of cohort studies for evaluating HRT and NSLCa in women, and a systematic review of case-control studies for association with HPV and NSLCa. Keywords: Lung neoplasms, Risk factor, Hormone replacement therapy, Human papillomavirus, Meta-analysis 국문요약 2002년에서 2012년간폐암통계를살펴보면비흡연여성에서선암종의발생이크게증가하는것으로확인된다. 이렇게여성에서비흡연폐암발생과관련한요인들로는호르몬대체요법 (HRT) 과인유두종바이러스 (HPV) 감염이알려져있다. 환자-대조군연구를이용한메타분석에따르면호르몬대체요법은폐암발생을억제하는것으로나왔다. HPV에대한메타분석은아직없는가운데위험요인으로의심하고있다. 따라서 HRT에대하여는코호트연구결과를이용한연합분석 (pooled analysis) 이필요하며, HPV에대하여는환자-대조군연구결과를이용한메타분석이수행될필요가있다. 중심어 : 폐암, 위험요인, 호르몬대체요법, 인유두종바이러스, 메타분석 2

4 폐암은한국인암사망의수위를차지하는원발암 (primary site cancer) 으로 [1], 흡연이폐암의주된발생요인으로보고있다 [2,3]. 국가통계포털 ( KOSIS) 과 한국중앙암등록본부 ( KCCR) 가제공한암발생및사망통계에따르면, 2002 년 부터 2012 년간암발생률과사망률에있어여자를기준으로남자의성비 (sex ratio) 가사망 률에서는변동이없는반면, 발생률에서는꾸준히감소하였다 (Fig. 1). 또한 KCCR 이제공한 폐암발생자의조직학적분포를살펴보면 (Fig. 2), 2002 년도기준으로남자에서가장많았 던편평세포암 (squamous cell carcinoma) 은꾸준히감소하는반면, 선암 (adenocarcinoma) 은꾸준히증가하여 2012 년 1 위가되었다. 여자에는 2002 년기준으로가장많았던선암은 그이후계속증가하여 2012 년현재여성폐암발생중 81% 를차지하였다. 이와더불어한 지역암센터에서치료한여성폐암대부분은비흡연자들 (73.0%) 이며, 비흡연자에서선암의 빈도가높다고보고하였다 [4]. 이상의두그래프와발표의의미는지난 10 년간비흡연여성에서예후가상대적으 로좋은선암의폐암발생이많아졌다는것으로요약할수있다. 이처럼평생을통해흡연 한적이없지만폐암이생기는경우 (Never-smokers lung cancer, NSLCa) 에있어, 여성, 아 시아인, 선종이더많다는점등 [5.6] 의역학적특성을보이면서새로운질병으로인식해야 한다는주장이제기되고있다 [7]. 3

5 NSLCa 위험요인으로알려진것들로는간접흡연 (second-hand smoking), 라돈 (radon), 석면 (asbestos), 조리시연기 (cooking fumes) 등의환경폭로, 유전적감수성 (genetic susceptability), 호르몬, 암유발바이러스 (oncogenic virus) 등이있다 [5,6,8]. 이들 중여성과밀접한관련이있다고보는것으로 (1) 간접흡연 (2) 조리시연기 (3) 호르몬 (4) 인유두종바이러스 (human papillomavirus, HPV) 감염으로좁힐수있다. 이중조리시연기나어릴때간접흡연은이미노출이되어서개입이불가능 (modifiable) 하다는점에서예방사업의효과는제한적이다. 이에더하여, Krishnan et al. [9] 은 NSLCa 의유전체분석을근거로흡연력이없는아시아인의폐암발생에있어간접흡연 가능성은낮다는주장을했다. 그렇지만일상생활속에서직장동료등주변으로부터의간 접흡연노출에대한예방적조치가필요한것은분명하다 [10]. 문제는간접흡연의노출정 도를측정하는방법론적한계때문에인과규명을위한역학연구수행이쉽지않다는점이 다 [11,12]. 여성호르몬에있어서는경구피임제 (oral contraceptives, OC) 와호르몬대체요법 (hormone replacement therapy, HRT) 를의심하는실험실적, 역학적, 임상적근거들을 Syegfried 가정리하였으며 [13], 이에대한메타분석들이수행되어왔다. Wu et al. [14] 은 OC 와폐암간의관련성을알아보기위하여 9 편의환자 - 대조군연구와 5 편의코호트연구결 과를선정하여체계적고찰을시행한결과관련성이없는것으로나왔다. 두가지연구설 계별로하부군분석 (subgroup analysis) 을했지만여전히의미를찾을수없었다. 그리고 4

6 HRT 와폐암간의관련성을알아본체계적고찰은 3 편이있다 [15-17]. 이들모두환자 - 대조 군연구결과의메타분석은보호효과가있으며통계적으로유의하게나왔다. 그러나코호 트연구에대한메타분석은일관성이없으면서통계적유의성을보이지않았다. 따라서 HRT 에대한여성폐암발생을규명하는코호트연구가추가로필요할뿐만아니라 [18], 기 존의발표된코호트추적자료들을모아연합분석 (pooled analysis) 을시행할필요가있다. 암유발바이러스중 HPV 감염이폐암발생과관련이있다고 1979 년 Syrjänen [19] 이 주장한이후, 폐암조직에서 HPV DNA 유병률 (prevalence) 에관한연구들이수행되었다. 이들에대한메타분석 [20-23] 결과, 발생한폐암의약 20% 에서 HPV 양성이며, 16 과 18 유 형이가장많이관여하는것으로보고되었다. 또한인과규명을위한환자 - 대조군연구의체 계적고찰에서 HPV 감염으로인한 SOR 이 5.67 배 (95% CI: ) 로보고하였다 [24]. 비흡연여성에있어서도여전히관련성이있다고나온다는점에서 [25], HPV 예방접종은자 궁경부암, 유방암 [26] 뿐만아니라, 폐암발생까지예방할가능성이열리게된다. 한편, 폐 암환자의혈액에서도 HPV 16/18 DNA 가검출된다는보고 [27] 에따르면, 비흡연여성에있 어폐암의조기진단으로도활용할가능성이있겠다 [28]. 지금까지비흡연여성에서의폐암발생에관여하는위험요인들중특히교정가능 한 (modifiable) 요인들인 HRT 복용력과 HPV 감염력에있어그관련성근거들을살펴보았 다. 향후의과제들로는 HRT 복용력에대하여코호트연구에대한연합분석이필요하며, HPV 감염력에대하여는환자 - 대조군연구에대한체계적고찰이필요하다. 이를통해만약 HRT 복용력이폐암발생의보호요인이고, HPV 감염력이위험요인이라면, 이를반영한보다 적극적인예방대책을수립할수있을것이다. 5

7 감사의글 폐암등록환자의 년도조직학적분류에관한정보제공에협조해준 한국중앙암등록본부에감사를표합니다. 6

8 References 1. Jung KW, Won YJ, Kong HJ, Oh CM, Cho H, Lee DH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in Cancer Res Treat 2015;4: Bae JM, Li ZM, Shin MH, Kim DH, Lee MS, Ahn YO. Lung cancer incidence by smoking status in Korean men: 16-years of observations in the Seoul Male Cancer Cohort Study. J Korean Med Sci 2013;28: Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011;32: Kang HW, Park CW, Kim WJ, Song SY, Na KJ, Jeong JU, et al. Never-smoker lung cancer is increasing. J Lung Cancer 2012;11:89-93.(Korean) 5. Subramanian J, Govindan R. Lung cancer in 'Never-smokers': a unique entity. Oncology 2010;24: Alberg AJ, Wallace K, Silvestri GA, Brock MV. Invited commentary: the etiology of lung cancer in men compared with women. Am J Epidemiol 2013;177: Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers a different disease. Nat Rev Cancer 2007;7: Planchard D, Besse B2. Lung cancer in never-smokers. Eur Respir J 2015;45: Krishnan VG, Ebert PJ, Ting JC, Lim E, Wong SS, Teo AS, et al. Whole-genome sequencing of asian lung cancers: second-hand smoke unlikely to be responsible for higher incidence of lung cancer among Asian never-smokers. Cancer Res 2014;74: Besaratinia A, Pfeifer GP. Second-hand smoke and human lung cancer. Lancet Oncol 2008;9: Jaakkola MS, Jaakkola JJ. Assessment of exposure to environmental tobacco smoke. Eur Respir J 1997;10: Kawaguchi T, Ando M, Kubo A, Takada M, Atagi S, Okishio K, et al. Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer. Clin Cancer Res 2011;17: Siegrfied JM. Smoking out reproductive hormone actions in lung cancer. Mol Cancer Res 2014;12(1): Wu W, Yin ZH, Guan P, Ren YW, Zhou BS. Association of oral contraceptives use and lung cancer risk among women: an updated meta-analysis based on cohort and case-control studies. Asian Pac J Cancer Prev 2014;15:

9 15. Oh SW, Myung SK, Park JY, Lym YL, Ju W. Hormone therapy and risk of lung cancer: a meta-analysis. J Womens Health 2010;19: Chen X, Cai L. Meta-analysis of the effects on hormone replacement therapy and oral contraceptives associated with female lung cancer risk. Wei Sheng Yan Jiu 2009;38: (Chinese) 17. Yao Y, Gu X, Zhu J, Yuan D, Song Y. Hormone replacement therapy in females can decrease the risk of lung cancer: a meta-analysis. PLoS One 2013;8:e Bae JM, Kim EH. Hormonal replacement therapy and risk of lung cancer in women: an adaptive metaanalysis of cohort studies. J Prev Med Public Health (in press) 19. Syrjänen KJ. Condylomatous changes in neoplastic bronchial epithelium. Report of a case. Respiration 메모 [ 배 1]: 게재확정이된것 년도 SR 확인되어보완 1979;38: Srinivasan M, Taioli E, Ragin CC. Human papillomavirus type 16 and 18 in primary lung cancers a meta-analysis. Carcinogenesis 2009;30: Hasegawa Y, Ando M2, Kubo A3, Isa S4, Yamamoto S4, Tsujino K5, et al. Human papilloma virus in nonsmall cell lung cancer in never smokers: a systematic review of the literature. Lung Cancer 2014;83: Klein F, Amin Kotb WF, Petersen I. Incidence of human papilloma virus in lung cancer. Lung Cancer 2009;65: Syrjänen K. Detection of human papillomavirus in lung cancer: systematic review and meta-analysis. Anticancer Res 2012;32: Zhai K, Ding J, Shi HZ. HPV and lung cancer risk: a meta-analysis. J Clin Virol 2015;63: Bae JM, Kim EH. Human papillomavirus infection and risk of lung cancer in never-smoking women: an adaptive meta-analysis for case-control studies. Epidemiol Health (pending) 26. Bae JM. Two hypotheses of dense breasts and viral infection for explaining incidence of breast cancer by age group in Korean women. Epidemiol Health 2014;36:e Chiou HL, Wu MF, Liaw YC, Cheng YW, Wong RH, Chen CY, et al. The presence of human papillomavirus type 16/18 DNA in blood circulation may act as a risk marker of lung cancer in Taiwan. Cancer 2003;97: Li YJ, Tsai YC, Chen YC, Christiani DC. Human papilloma virus and female lung adenocarcinoma. Semin Oncol 2009;36:

10 sex ratio (man/woman) incidence mortality year incidence mortality Fig 1. Trends of sex ratios in incidence and morality rates of lung cancers in Koreans during 2002 and Sources: KOSIS [ and KCCR [

11 90% 80% 70% 60% 50% 40% 30% 20% Sq Sq Ad Ad Sm Sm Lg Lg 10% 0% Fig 1. Trends of the histological proportion (%) of lung cancers in Koreans during 2002 and Sources: KCCR [ M(men) W(women) Sq (squamous cell carcinoma) Ad (adenocarcinoma) Sm (small cell carcinoma) Lg (large cell carcinoma)

[별지6호] 최종보고서 서식

[별지6호] 최종보고서 서식 비흡연여성의폐암발생과관련한교정가능위험요인 Modifiable Risk Factors of Lung cancer in Never-Smoker Women 1 국문요약 2002년에서 2012년간폐암통계를살펴보면비흡연여성에서선암종의발생이크게증가하는것으로확인된다. 이렇게여성에서비흡연폐암발생과관련한요인들로는호르몬대체요법 (HRT) 과인유두종바이러스