<Hypothesis> 췌장암발생예방에있어 알레르기질병력과감귤섭취의상호작용규명을위한관찰연구필요성 It needs an observational study for Interaction of Allergic History and Citrus Fruit Intake as a Protective Factor in Pancreatic cancer
Abstract While the main product of Jeju islands is citrus fruit and the prevalence of atopic dermatitis of dweller s students is relatively higher, the incidence of pancreatic cancer showed the lowest in Korea. The systematic reviews reporting allergic history and intake of citrus fruit as protective factors of pancreatic cancer (PCC) were published in 2005 and 2008, respectively. Although there were discrepancies in results of subgroup analyses between case-control studies and cohort studies, it is necessary to evaluate an interaction effect of allergic history and intake of citrus fruits in PCC risk. Key words: Pancreatic neoplasms, Risk factor, Allergy and immunology, Citrus, Meta-analysis
서론 췌장암 (pancreatic cancer) 은북미에서암사망률순위 4 위에속하는원발암 (primary site cancer) 이며 [1], 5 년생존률이 5% 미만인대표적인악성종양이다 [2]. 한국인에 서도 2011 년도췌장암사망률은십만명당 5.6 명으로, 암사망률에있어폐암, 간암, 위암다 음으로 4 위를차지하며, 지난 10 년간의 5 년생존율개선이없는유일한원발암이다 [3]. 따 라서췌장암의발생위험증가혹은감소요인을규명하는분석역학 (analytical epidemiology) 연구가절실히필요하다 [4]. 지금까지알려진개입가능한위험요인 (risk factors) 들로는흡연, 식이, 질병력등이있으며 [5], 이중에서체계적고찰 (systematic reviews, SR) 을수행하여유의미한 (significant) 연구결과를확인한요인으로는알레르기질 병력 [6] 과감귤섭취 [7] 가있다. 한편대한민국의지방자치단체중가장낮은위도에위치한제주도는전국에비하 여췌장암발생률이현저하게낮다 [8]. 그런데, 제주도는감귤의주요생산지이면서, 초중고 등학생에있어아토피피부염수진률이전국에서가장높은지역으로알려져있다 [9]. 이런 보건환경적인사실들을감안할때, 저자는감귤섭취와알레르기질병력의상호작용이췌장 암발생률을낮춘다는가설을제시할수있는가를검토해보았다.
본문 가. 알레르기질병력의발생억제효과 2005 년도발표된 Gandini et al. [6] 이수행한췌장암에있어알레르기질병력의영 향에대한 SR 에서, 10 편의환자 - 대조군연구 (case-control studies, CCS) 와 4 편의코호트연 구 (cohort studies, COS) 의메타분석결과는총상대위험도 (summary relative risk, srr) 0.82, 95% 신뢰구간 (confidence intervals, CIs) 0.68-0.99 로췌장암발생을억제하는것으로 나왔다. 그런데, 4 편의 COS 각각의결과들 [10-13] 은통계적유의성을보이지않았다. PubMed (National Library of Medicine, US) 에서제공하는 Related citations 기능을 활용하여 4 편의 COS 각각의검색목록을만든다음, 일일이손으로검색하였다 [14,15]. 그 결과, 2005 년도에발표된두편의 COS 논문 [16,17] 을추가로확보하였다. 반면 2006 년도이 후발표된코호트연구는찾을수없었다. Fig 1 은총 6 편의선정대상논문들의로그화상 대위험도 (logrr) 과이의표준오차 (SElogRR) 을활용하여메타분석결과로얻어낸 forest plot 이다. 이질성수준을나타내는 I-square [18] 수치 26.4% 에서고정효과모형을적용한 srr 은 1.15 (95% CI: 0.77-1.71) 로통계적유의성이없었다. Begg s test 수행결과 p- 값은 0.71 로소규모연구에영향을받지않았으며, 해당 funnel plot 상대칭성을해치지는않았 다 (Fig 2). 나. 감귤섭취의발생억제효과 2009 년도발표된 Bae et al. [7] 이수행한췌장암에있어감귤섭취의영향에대한 SR 에서도 4 편의 CCS 와 5 편의 COS 를합친메타분석결과는암발생감소효과가있는것으로
나왔다 (srr=0.83, 95% CI, 0.70-0.98). 그러나 5 편의 COS 연구결과에대한하부군분석 (subgroup analysis) 에서 srr 은 0.97 (95% CI, 0.86-1.10) 으로통계적유의성이없었다. PubMed 의 Related citations 기능을활용하여 5 편의 COS [19-23] 각각의검색목 록을만든다음, 일일이손으로검색하였다 [14,15]. 그결과, 6 편의 COS 논문 [24-29] 을추가 로확보하였다. 그런데 Stolzenberg-Solomon et al. [20] 논문과 Bobe et al. [24] 논문의코호 트는동일한것으로확인되어, 2008 년도발간된논문 [24] 을분석대상으로선정하였다. 또한 Shigihara et al. [28] 논문과 Lie et al. [29] 논문의코호트구성원도동일하여, 이중 2014 년도 에발간된논문 [28] 을선정하였다. 또한 Coughlin et al. [19] 논문은암사망률을다룬논문이 었다. 따라서총 8 편 [21-28] 을메타분석의대상으로삼았다 이중남녀별로 RR 을제시한논문 2 편 [21,28] 은성별결과를메타분석하여얻은 srr 과 95% CI 을적용하였다. Fig. 3 은그결과로얻어낸 forest plot 이다. 이질성수준을나 타내는 I-squared [18] 수치 25.9% 에서고정효과모형을적용한 srr 0.99 (95% CI: 0.93-1.05) 로통계적유의성이없었다. Begg s test 결과 p- 값은 0.45 으로소규모연구에영향을받지 않았으며, 해당 funnel plot 상대칭성을해치지는않았다 (Fig 4).
결론및제언 알레르기질병력과감귤섭취모두 COS 연구들의 SR 결과에서통계적유의성을확보 하지않았다. CCS 와 COS 로나누어하부군분석을한결과가서로상반되는경우는, 근거의 계층에따라 CCS 보다는 COS 의 SR 결과를우선수용하는것이타당할것이다 [30]. 그렇지만인과성규명을위한분석역학연구에서췌장암처럼발생률이낮은희귀질환 (rare diseases) 을다룰경우는 COS 연구수행시대규모의관찰대상자를확보해야하는만 큼, CCS 연구설계를우선추천한다. 반면 CCS 인경우노출력에대한회상오류 (recall bias) 가 개입될수있다는문제때문에 [31], 최근에는연구대상자규모를증대시킨통합분석 (pooled analysis) 연구를수행하고있다. 즉, 감귤에있어메타분석결과 [7] 가보고된이후, 감 귤성분에대한실험실적연구들 [4] 이발표되는한편, 14 개의코호트를모은통합분석결과 는통계적유의성이없었다 [26]. 알레르기질병력의메타분석 [6] 이 2005 년보고된이후, 10 개 의 CCS 를모아서통합분석 (pooled analysis) 를시행했을때, 발생위험감소효과가있는것으 로나왔다 [32]. 그러나코호트를모은통합분석결과는아직발표된것이없다. 물론, COS 연구라해도노출력에대한측정오류 (measurement error) 의가능성이여전 히있다. 예를들어역학연구에서알레르기질병력과식이섭취수준을대부분자기보고식 (self-reported) 응답에의존하고있으며 [26,31], 추적기간의부족과추적소실 (follow-up loss) 등의방법론적한계는인과성규명을어렵게한다 [33]. 또한메타분석에적용하는노출 수준은섭취량의분포에따른상대적수준을다루기때문에, 노출수준에있어코호트간에 일관성을확보하기가어렵다.
현재로는 CCS 연구결과들의 SR 은일관되게암발생위험을낮추는것으로보고되면서, 전문가종설 (expert review) 에서는감귤섭취 [4] 와알레르기질병력 [31,32] 은췌장암의발생 억제효과가있다고해석하고있다. 그렇다면제주도의췌장암발생현황을고려할때알레 르기질병력과감귤섭취의상호효과에대한가설규명은필요하다고볼수있다. 지금까지 국내외를통틀어알레르기질병력과감귤섭취의상호작용에따른췌장암억제효과에대한 분석역학연구는아직보지못하였다. 두설명변수를모두확보한코호트에서이의상호효 과에대한분석을시도하기를제안한다. 감사의글 이논문은 2015 학년도제주대학교학술진흥연구비지원사업에의하여연구되었음
References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29. 2. Klapman J, Malafa MP. Early detection of pancreatic cancer: why, who, and how to screen. Cancer Control 2008;15:280-287. 3. Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2011. Cancer Res Treat 2014;46:109-123. 4. Pericleous M, Rossi RE, Mandair D, Whyand T, Caplin ME. Nutrition and pancreatic cancer. Anticancer Res 2014;34:9-21. 5. Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20:197-209. 6. Gandini S, Lowenfels AB, Jaffee EM, Armstrong TD, Maisonneuve P. Allergies and the risk of pancreatic cancer: a meta-analysis with review of epidemiology and biological mechanisms. Cancer Epidemiol Biomarkers Prev. 2005;14:1908-1916. 7. Bae JM, Lee EJ, Guyatt G. Citrus fruit intake and pancreatic cancer risk: a quantitative systematic review. Pancreas 2009;38:168-174. 8. Bae JM. Explaining cancer incidence in the Jejudo population. J Prev Med Public Health 2009;42:67-72. (Korean) 9. Bae JM, Shin KS. Estimating the prevalence of atopic dermatitis in school students of Jejudo, Korea. J Prev Med Public Health 2009;42:171-176. (Korean) 10. McWhorter WP. Allergy and risk of cancer. A prospective study using NHANESI followup data. Cancer 1988;62:451-455. 11. Mills PK, Beeson WL, Abbey DE, Fraser GE, Phillips RL. Dietary habits and past medical history as related to fatal pancreas cancer risk among Adventists. Cancer 1988;61:2578-2585. 12. Eriksson NE, Holmén A, Högstedt B, Mikoczy Z, Hagmar L. A prospective study of cancer incidence in a cohort examined for allergy. Allergy 1995;50:718-722. 13. Stolzenberg-Solomon RZ, Pietinen P, Taylor PR, Virtamo J, Albanes D. A prospective study of medical conditions, anthropometry, physical activity, and pancreatic cancer in male smokers (Finland). Cancer Causes Control 2002;13:417-426. 14. Bae JM. Narrative reviews. Epidemiol Health 2014;36:e2014018. 15. Bae JM. Human papillomavirus 16 infection as a potential risk factor for prostate cancer: an adaptive meta-analysis. Epidemiol Health 2015;37:e2015005. 16. Eriksson NE, Mikoczy Z, Hagmar L. Cancer incidence in 13811 patients skin tested for allergy. J Investig
Allergol Clin Immunol 2005;15:161-166. 17. Hagströmer L, Ye W, Nyrén O, Emtestam L. Incidence of cancer among patients with atopic dermatitis. Arch Dermatol 2005;141:1123-1127. 18. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-1558. 19. Coughlin SS, Calle EE, Patel AV, Thun MJ. Predictors of pancreatic cancer mortality among a large cohort of United States adults. Cancer Causes Control 2000;11:915-923. 20. Stolzenberg-Solomon RZ, Pietinen P, Taylor PR, Virtamo J, Albanes D. Prospective study of diet and pancreatic cancer in male smokers. Am J Epidemiol 2002;155:783-792. 21. Lin Y, Kikuchi S, Tamakoshi A, Yagyu K, Obata Y, Inaba Y, et al. Dietary habits and pancreatic cancer risk in a cohort of middle-aged and elderly Japanese. Nutr Cancer 2006;56:40-49. 22. Larsson SC, Håkansson N, Näslund I, Bergkvist L, Wolk A. Fruit and vegetable consumption in relation to pancreatic cancer risk: a prospective study. Cancer Epidemiol Biomarkers Prev. 2006;15:301-305. 23. Nöthlings U, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Dietary glycemic load, added sugars, and carbohydrates as risk factors for pancreatic cancer: the Multiethnic Cohort Study. Am J Clin Nutr 2007;86:1495-1501. 24. Bobe G, Weinstein SJ, Albanes D, Hirvonen T, Ashby J, Taylor PR, et al. Flavonoid intake and risk of pancreatic cancer in male smokers (Finland). Cancer Epidemiol Biomarkers Prev 2008;17:553-562. 25. Vrieling A, Verhage BA, van Duijnhoven FJ, Jenab M, Overvad K, Tjønneland A, et al. Fruit and vegetable consumption and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2009;124:1926-1934. 26. Koushik A, Spiegelman D, Albanes D, Anderson KE, Bernstein L, van den Brandt PA, et al. Intake of fruits and vegetables and risk of pancreatic cancer in a pooled analysis of 14 cohort studies. Am J Epidemiol 2012;176;373-386. 27. Heinen MM, Verhage BA, Goldbohm RA, van den Brandt PA. Intake of vegetables, fruits, carotenoids and vitamins C and E and pancreatic cancer risk in The Netherlands Cohort Study. Int J Cancer 2012;130:147-158. 28. Shigihara M, Obara T, Nagai M, Sugawara Y, Watanabe T, Kakizaki M, et al. Consumption of fruits, vegetables, and seaweeds (sea vegetables) and pancreatic cancer risk: the Ohsaki Cohort Study. Cancer Epidemiol 2014;38:129-136. 29. Li WQ, Kuriyama S, Li Q, Nagai M, Hozawa A, Nishino Y, et al. Citrus consumption and cancer incidence: the Ohsaki cohort study. Int J Cancer 2010;127:1913-1922. 30. Health Sciences Library, UNC-Chapel Hill. Type of Questions and studies. [cited 2015 Apr 13].
Available http://www.hsl.unc.edu/services/tutorials/ebm/supplements/questionsupplement.htm. from: 31. Turner MC, Chen Y, Krewski D, Ghadirian P. An overview of the association between allergy and cancer. Int J Cancer 2006;118:3124-3132. 32. Rittmeyer D, Lorentz A. Relationship between allergy and cancer: an overview. Int Arch Allergy Immunol 2012;159:216-225. 33. Olson SH, Hsu M, Satagopan JM, Maisonneuve P, Silverman DT, Lucenteforte E, et al. Allergies and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium. Am J Epidemiol 2013;178:691-700.