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1 < 체계적고찰 > 인유두종감염과비흡연자및여성폐암발생관련성 : 개작 메타분석 Human Papillomavirus Infection and Risk of Lung cancer in Never-smokers and Women : An Adaptive Meta-Analysis

2 Abstract Objectives: Occurrence of lung cancers in Koreans is increasing in women with never smoking history. Human papillomavirus (HPV) infection is suggested as a modifiable risk factor of lung cancer in never-smokers and women (LCNSW). This systematic review (SR) aimed to evaluate an association between HPV infection and lung cancer risk in LCNSW. Methods: Based on a SR and some expert reviews, we made the list of refereed, cited, or related articles using the PubMed and Scopus databases. All of the case-control studies that obtained the odds ratio of HPV infection in LCNSW were selected. Estimate of summary odds ratio (SOR) with 95% confidence intervals (CI) were calculated. Results: Total 4 case-control studies were finally selected. The fixed effect model was applied because of homogeneity (I-squared = 0.0%). The SORs in women and in nonsmokers were 5.40 (95% CI: ) and 4.81 (95% CI: ), respectively. Conclusions: These results showed a significant effect of HPV infection in LCNSW. It would be an evidence for necessary to set up a preventive plan against LCNSW. Keyword: Lung neoplasms, Risk factor, Human Papillomavirus, Meta-analysis

3 Introduction 폐암 (lung cancer) 은한국인암사망의수위를차지하고있어질병부담이가장큰 원발암이다 [1]. 국가통계기관이제공한 년폐암발생현황을살펴보았을때, 여성 에서의발생률증가와함께선암 (adenocarcinoma) 의비중이높아졌다 [2]. 이런사실은한 지역암센터에서치료한폐암환자들에서도확인되며 [3], 특히여성폐암대부분은비흡연 자들 (73.0%) 로보고하였다. 이렇게여성비흡연자의폐암발생이증가하는추세는전세계적으로나타나는현상 으로 [4-5], 비흡연자들의폐암은흡연자의폐암과다른질병으로보아야한다는주장이제 기되고있다 [6-8]. 여성비흡연자들의폐암에대한원인가설들중우선적으로제기되는 것은간접흡연 (second-hand smoking) 이다 [6,7,9-11]. 그러나아시아인의비흡연폐암발생 에서간접흡연이관여할가능성이낮다는유전체연구보고 [12] 가있을뿐만아니라, 간접 흡연을통제하는것은본인의노력만으로는어렵고사회공동체가노력해야한다는점에서 암예방대책에한계가있다. 대신개입가능 (modifiable) 한위험요인들중의하나로인유두 종바이러스 (human papilloma virus, HPV) 감염이다 [6,7,9]. 자궁경부암 [13], 전립선암 [14], 유방암 [15] 등의위험요인으로써, 현재상용화된예방백신이있기때문이다 [16]. HPV DNA 가폐암조직의약 20% 에서검출되며 [17-20], 아시아인의폐암조직에서 더높은검출률을보이고있다 [21-24]. 한국인폐암에서는 HPV 33 아형의검출률이 31.3%

4 임을보고하였다 [25] 년도에발표된체계적고찰연구에따르면 [26], HPV 감염으로인 한발생위험도 (odds ratio, OR) 가 5.67 배 (95% confidence intervals, CI: ) 이며, 아 시아인들에서는 6.23 배 (95% CI: ) 배로다른인종에비하여더높았다. 그런데, 해 당연구에서여성과비흡연자에서의위험도가얼마인지에대한하부군연구 (sub-group analysis) 는제시하지않았다. 따라서본연구의목적은여성및비흡연자에서 HPV 감염과 폐암발생의관련성을알아보는체계적고찰연구를수행하는것이다.

5 Subjects & Methods 가. 관련한논문검색및선정 기존에수행된체계적고찰논문을검색에최대한활용한다는점에서, 전자검색이 아닌손검색 (hand search) 전략을적용하였다 [14, 27, 28]. 즉, 5 개의체계적고찰논문을 중심으로참고문헌 (references) 들을탐색하고, 논문별로 PubMed ( 와 Scopus ( 데이터베이 스가제공하는 Cited articles 와 Similar (Related) articles 의목록을확보하였다. 연구목적을위해비흡연자및여성에있어 HPV DNA 검사를시행한환자 - 대조군연구가선정기준이다. 따라서, 우선수합된목록의논문별로초록및본문내용에 서다음의 3 가지제외조건들을적용하였다. (1) 가설이다른경우 (2) 전문가종설혹은체 계적고찰 (3) 환자사례연구. 이를적용하고남은환자 - 대조군연구논문에있어 (4) 환자 - 대조군연구이지만병리조직에서 HPV DNA 를확인하지않는경우 (5) 환자 - 대조군연구이지 만여성및비흡연자에대한정보를얻어낼수없는경우를적용하여분석대상이될논 문을최종선정하였다. 나. 통계분석

6 각논문별로제외기준의적용과 HPV 관련정보확보를두연구자가진행하였다. 확보한대상군과 HPV 양성자의수치를통해 OR 과 95% CI 을구하였다. 이질성여부확인은 I-squared 값 (%) 을기준으로평가하였으며, 동질성이확보될경우고정효과모형 (fixed effect model) 에따른총교차비 (summary odds ratio, SOR) 와이의 95% CI 을구하는메타분석을 시행하였다. 통계적유의수준을 5% 로정했으며, MedCalc version 15.8 ( 통 계프로그램을이용하였다.

7 Results Figure 1 은메타분석을위한최종선정과정을나타낸것이다. HPV 와폐암간의유병 률 (prevalence) 과위험도 (risk ratio) 를알아보기위하여진행된체계적고찰 5 편을기준 으로이의참고문헌 136 편과, PubMed 와 Scopus 를활용한인용 (cited) 과관련 (related) 문헌은 1,219 편을확보하였다. 총 1,355 편에있어선정기준을적용하였을때, (1) 가설이 다른경우 1,219 편 (2) 전문가종설혹은체계적고찰 19 편 (3) 환자사례연구 96 편 (4) 환자 - 대조군연구이지만병리조직에서 HPV DNA 를확인하지않는 6 편 (5) 환자 - 대조군연구이지 만여성혹은비흡연에대한정보를얻어낼수없는 11 편을제외시켰다. 따라서총 1,351 편이제외되어최종적으로 4 편이선정되었다 [29-32]. Table 1 은최종선정된 4 편의환자 - 대조군연구논문에있어, 대상자의국적, 검사 시료, 여성혹은비흡연군에따른환자군과대조군의분포를정리하였고, HPV DNA 양성여 부에따라산출된 OR 및 95% CI 이다. 여성군과비흡연군각각 3 편의정보를가지고있었 으며, 두군모두에서 I-squared 값이 0% 로동질하였다 (Figure 2). Table 2 는 HPV DNA 16/18 아형에있어고정효과모형을적용한메타분석결과를제시한것이다. 여성군의 SOR 은 5.40 (95% CI: ) 로, 비흡연군의 SOR 4.81 (95% CI: ) 으로통계적유의 성을보였다.

8 Discussion HPV 감염에따른폐암발생 SOR 은여성군 5.397, 비흡연군 로산출되었다. 이 는남녀를나누지않을경우 SOR 5.67 과유사한수준이다 [26]. 추가로여성비흡연자에서 18 아형감염은 배 (95% CI: ) 위험하다는보고 [29] 를감안하면 (Table 2), 실제의위험도는더높을것으로예상된다. 이런결과들에따르면, HPV 감염을예방하는백 신접종은향후여성의폐암발생까지도줄일수있다는근거가된다. 또한, 남녀를구분하 지않은경우와여자로제한한경우의 SOR 이유사한사실에서, HPV 감염이흡연남성보다 는비흡연여성의폐암발생에더큰비중으로작용한다고유추할수있겠다 [33,34]. 이번체계적고찰에선정된 4 편 [29-32] 은모두환자 - 대조군연구이었다. HPV DNA 실험을위해서는코호트연구를수행하기어렵기때문으로판단된다. 선정된 4 편중 3 편 [29,30,32] 은 Zhai et al. [26] 논문의분석대상으로선정된것이다. 나머지 Yu et al. [31] 논문 은같은저자들의 2013 년도발표논문 [35] 대신하여선정된것은, 자군에대한분석정보 를갖고있었기때문이다. 이처럼논문이추가되지않은것은본연구의검색마감시점이 2015 년 9 월인반면, Zhai et al. [26] 연구는 2014 년 3 월이기때문이다. 향후여성비흡연자 에서의폐암발생에대한연구가보다집중적으로이루어질필요가있다. 한편이번손검색을통해 Zhai et al. [26] 체계적고찰에서선정기준에맞지만선정

9 되지않은논문네편을확보할수있었다 [36-39]. 검색종료인 2014 년 3 월을기점으로그 이후에발표된두편 [38,39] 이있는반면, 그이전에발표된두편 [36,37] 이있다는점에 서손검색의중요성이강조된다. 이중 Yu et al. [39] 은동일한자료원에서동일한저자가 발표했던두편의논문 [31,35] 과중복되어, 향후메타분석을수행할때대상자선정에유의 할필요가있다. 폐조직에서의 HPV DNA 검출이가장민감한것으로알려진가운데 [24], 기관지 세척액이나혈액에서 DNA 혹은항체검출로 PV 감염여부를적용한환자 - 대조군연구 6 편이검색과정에서분석대상에서제외되었다 [40-45]. 이처럼조직이아니라혈액을이용 하여 HPV 감염여부를알아보는시도는, 향후비흡연여성에있어폐암의조기검진에도활 용할가능성이있겠다 [2]. 또한경구피임제 (oral contraceptives) 복용이 HPV 증식에관여 한다는주장 [46] 이있어, 호르몬제복용에의한폐암발생위험에대하여도추가적인연구 가필요하다 [47,48]. 향후비흡연자의폐암발생이심각한문제가될것을예상하고 [49], 이에대한예방대책을수립하는노력이다각도로있어야할것이다. 특정바이러스가암을유발함을입증하려면필요한기준들 [50] 을만족시키기위해 서는환자사례연구가아니라환자 - 대조군연구를수행해야한다 [51]. 그러나암조직을활 용한환자 - 대조군연구 (tumor-based case-control study) 는측정오류를범하기쉽다는단 점이있다 [52,53]. 이를극복하기위하여지속적인 adaptive Systematic reviews (SR) 연구가

10 필요하다.

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[별지6호] 최종보고서 서식

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