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1 Korean J Gastroenterol Vol. 60 No. 1, ORIGINAL ARTICLE 대장암의가족력이대장선종발생에미치는영향 최민영 1,3, 김병관 1,3, 김지원 1,3, 이국래 1,3, 정지봉 1,3, 이재경 1,3, 정용진 1,3, 김원 1,3, 안동원 1,3, 김영훈 1,3, 주세경 1,3, 장미수 2,3, 권형주 2,3 서울대학교보라매병원내과 1, 병리과 2, 서울대학교의과대학내과학교실 3 The Effects of Family History of Colorectal Cancer on the Development of Colorectal Adenoma Min Young Choi 1,3, Byeong Gwan Kim 1,3, Ji Won Kim 1,3, Kook Lae Lee 1,3, Ji Bong Jeong 1,3, Jae Kyung Lee 1,3, Yong Jin Jung 1,3, Won Kim 1,3, Dong Won Ahn 1,3, Young Hoon Kim 1,3, Sae Kyung Joo 1,3, Mee Soo Chang 2,3 and Hyeoung Ju Kwon 2,3 Departments of Internal Medicine 1 and Pathology 2, Seoul National University Boramae Hospital, Department of Internal Medicine, Seoul National University College of Medicine 3, Seoul, Korea Background/Aims: Early detection of polyp is important for the prevention of colorectal cancer (CRC). There have been few studies to investigate the relationship between colorectal adenoma and family history of CRC (FHCRC) in Korea. The aim of this study was to identify the relationship between colorectal adenoma and FHCRC. Methods: Between March 2009 and September 2010, 225 patients with adenomatous polyps were included. Their medical records with clinical history and size, numbers, histology of polyps were reviewed. Immunohistochemical staining using Bcl-2, Bax, p-akt, NF-κB, and β-catenin antibodies were performed. We compared the histology of adenoma and expression of immunohistochemical staining according to the existence of FHCRC. Results: The incidence of colorectal adenoma increased in case of FHCRC (p=0.029). In patients with FHCRC, the mean age of patients was 49 years old and younger than patients without FHCRC. In addition in patients with FHCRC, the incidence of advanced adenoma was significantly higher than in patients without FHCRC (p=0.001). The expression of Bax was significantly lower in patients with FHCRC than without FHCRC (p=0.046). Conclusions: There was a tendency for polyp to develop in their younger ages and to be more advanced adenomas in patients with FHCRC. The low expression of Bax, tumor suppressor gene, might be associated with the development of polyps in patient with FHCRC. Therefore, patients with FHCRC may be better to start screening colonoscopy earlier than patient without FHCRC. (Korean J Gastroenterol 2012;60:36-41) Key Words: Colorectal neoplasms; Colorectal adenoma; Family history of colorectal cancer; Bcl-2-associated X protein 서론 대장암은서구에서암사망률 2위를차지할정도로발생빈도가높은암이다. 식생활이서구화되면서대장암은국내에서도급격히증가하여한국인암종의약 12.7% 를차지하고암으로인한전체사망원인중남자는 4위, 여자는 3위를차지 한다. 1 대장암의발생기전은 1951년 Jackman과 Mayo 2 가 adenoma-carcinoma sequence 학설을처음제시한후이를뒷받침하는여러연구들이발표되었으며, 현재대부분의대장암은대장선종에서발생하는것으로알려져있다. 3 전암병변으로부터의대장암의발생과진행은성장촉진신호의증가, 성장억제신호의감소, 증식, 전이등이관여하는일련의유 Received January 25, Revised April 18, Accepted April 21, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 김병관, , 서울시동작구보라매로 5길 20, 서울대학교보라매병원내과 Correspondence to: Byeong Gwan Kim, Department of Internal Medicine, Seoul National University Boramae Hospital, 5-gil 20, Boramae-ro, Dongjak-gu, Seoul , Korea. Tel: , Fax: , byeonggwankim@gmail.com Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 60 No. 1, July

2 Choi MY, et al. The Effects of Family History of Colorectal Cancer on the Colorectal Adenoma 37 전적변화의축적에의해다단계과정을밟게된다. 4 그러나이런유전자들의변이는환자에따라발현양상의차이가있고이로인해대장암의생물학적특성이달라질수있어특정유전자의발현여부및정도는예후와연관되기도한다. 5 대장암의예방및치료를위해서는전암병변인선종을미리발견하여제거하는것이가장중요하기때문에대장암의위험요인인가족력, 염증성장질환, 유전성용종증등에해당되는환자는더젊은나이에대장내시경을시행받도록권고되고있다. 대장암의가족력이대장선종의발생에미치는영향에대한국내외의몇몇연구들이있지만아직논란이많은상태로어떠한연관성이있는지뚜렷하게밝혀지지않았으며특히면역조직화학염색을시행하여연관성을분석한국내연구는아직없었다. Nuclear factor kappa B (NF-κB) p65는암세포의성장및사멸에관여하고 β-catenin과 phosphorylated-akt (p-akt) 및 Bcl-2도세포증식에관여하여암발생에중요한역할을한다. 6,7 이와대조적으로 p53과 Bcl-2-associated X protein (Bax) 는암세포의성장을억제하는것으로알려져있다. 8 이번연구는대장암의가족력이대장선종발생과상관관계가있는지를알아보고, 대장암의가족력에따라세포증식혹은억제에관여하는여러신호전달인자의발현에차이가있는지를알아보고자하였다. 대상및방법 1. 대상이번연구는병원윤리위원회의승인을받았으며 2009년 3월부터 2010년 9월까지서울대학교보라매병원건강검진센터를방문하여대장내시경을시행받은 1,123명중대장선종이발견된 225명을대상으로하였다. 대장폴립의과거력이있는환자, 염증성장질환등의대장질환이있는환자및악성종양의과거력이있는환자는연구에서제외하였다. 2. 방법 1) 대장내시경시행및폴립의관찰과생검환자들은대장정결을위해검사전날 polyethylene glycol (TaeJoon Pharmaceuticals, Seoul, Korea) 4 L를복용하였다. 검사시행전통증완화를위해 pethidine hydrochloride (Ha Na Pharmaceuticals, Seoul, Korea) 50 mg을근육주사하고수면유도제는 midazolam (Bukwang Pharmaceuticals, Seoul, Korea) 을사용했으며대장내시경검사는 2명의숙련된소화기내과전문의가시행하였다. 모든폴립들은조직학적검사를위해생검이시행되었으며병변의크기및개수등을기록지에기록하였다. 2) 임상기록및병리조직검토환자의임상기록을토대로성별, 연령및 BMI를조사하고대장암의가족력이직계가족에서있는경우를가족력있음, 그외에는가족력없음으로분류하였다. 생검한폴립으로제작된병리슬라이드의검토는 2명의숙련된병리과전문의가시행하였다. 조직학적으로융모형조직의포함유무에따라관상형과융모형으로분류하였고이형성은저등급및고등급으로분류하였다. 융모형또는크기가 10 mm 이상인폴립및고등급이형성을가진폴립은진행성선종 (advanced adenoma) 으로정의하였다. 3) Tissue microarray 제작및면역조직화학염색대장선종으로진단된환자중대장암가족력이있는경우를환자군으로설정한후대장암의가족력이없는나머지중에서이들과동일한연령대와성별을가진같은수의대조군을설정하여면역조직화학염색을시행하였다. Tissue microarray 제작을위해파라핀에고정된조직을 0.6 mm 지름의실린더로천공한후떼어서 tissue arrayer를이용하여다른 recipient의파라핀블록으로옮겨심었다. 그후환자군및대조군의폴립조직에대하여 p-akt (Epitomics Inc., Burlingame, CA, USA; 희석배율, 1:200), β-catenin (BD Transduction Laboratories, Franklin Lakes, NJ, USA; 희석배율, 1:800), NF-κB p65 (Abcam Inc., Cambridge, MA, USA; 희석배율, 1:200), Bax (Epitomics Inc; 희석배율, 1:200), Bcl-2 (Dako A/S, Glostrup, Denmark; 희석배율, 1:100) 항체를이용한면역조직화학염색을 autostainer 로시행하였다. Leica bond-max stainer (Leica Microsystems, Wetzlar, Germany) 를사용하여탈파라핀과함수과정, 3% 과산화수소수처리를거쳐 100 o C에서 20분간가열후세척을마쳤다. 이후 bond polymer kit (Leica Microsystems) 를적용하여 polymer detection 방법으로반응시켰고발색제로는 3,3-diamino-benzidine-tetrahydrochloride (Dako A/S) 를반응시켜세척하였으며 Mayer s hematoxylin (BBC Biochemical, Stanwood, WA, USA) 대조염색을실시하여광학현미경하에관찰하였다. 4) 면역조직화학염색의결과판정염색결과의판독은 2명의병리전문의에의하여시행되었으며 40배, 100배광학현미경소견하에서판독하였다. Bcl-2 와 Bax는세포질내에서갈색으로염색되는세포가종양세포의 10% 미만일때를 0, 10-25% 인경우를 +1, 26-49% 인경우를 +2, 50% 이상의세포에서염색이된경우를 +3으로판정하여 4등급으로구분하였다. 9,10 p-akt는전혀염색되지않은경우를 0, 50% 미만의약한염색강도를보인경우를 +1, 50% 이상의약한또는중등도의염색강도를보인경우를 +2, 50% 이상의강한염색강도를보인경우를 +3으로 Vol. 60 No. 1, July 2012

3 38 최민영등. 대장암의가족력이대장선종발생에미치는영향 판정하였다. 11 NF-κB p65는세포질과핵모두에염색되는세포의수가 10% 이상이면양성으로, 그외는음성으로판정하였다. 12 β-catenin은세포막에 10% 이상발현되나핵에는 10% 미만으로염색되는정상발현의경우를음성으로, 세포질또는핵에 10% 이상염색되거나또는염색이소실되는이상발현의경우를양성으로판정하였다. 5,13 통계학적인비교분석을위해 Bax, Bcl-2, p-akt는 0, +1을약양성발현군 (low) 으로, +2, +3을강양성발현군 (high) 으로구분하였다. 10 5) 통계분석 통계분석은 SPSS version 14.0 (SPSS Inc., Chicago, IL, USA) 을이용하였고, 95% 의신뢰수준을가지고양측검정을실시하였으며유의수준은 p<0.05로하였다. 전체환자중에서대장암의가족력에따른대장선종발생의연관성을알아보기위해 chi-square test를실시하였고대장선종환자를대장암가족력유무에따라두군으로나누어임상적특징및폴립의개수, 크기, 조직학적형태, 이형성등과의상관관계분석을위해 Mann-Whitney test를실시하였다. 그리고대장선종 Table 1. The Relationship of Colonic Adenoma with Family History of Colorectal Cancer Family history of colorectal cancer Yes (n=47) No (n=1,076) Yes (n=225) 11 (35.5) 214 (19.6) Values are presented as n (%). Colonic adenoma No (n=898) 20 (64.5) 878 (80.4) p-value Table 2. Characteristics of the Patients with Colonic Adenoma according to Family History of Colorectal Cancer Family history of colorectal cancer Yes (n=11) No (n=214) p-value Age (yr) 49.0± ± Sex (male/female) 9/2 162/ Body mass index (kg/m 2 ) 24.4± ± Polyp number (81.8) 159 (74.3) (18.2) 44 (20.6) 6 0 (0.0) 11 (5.1) Polyp size (mm) <5 4 (36.4) 96 (44.9) 5 and <10 4 (36.4) 96 (44.9) 10 3 (8.9) 19 (8.9) Histology Tubular adenoma 8 (72.7) 207 (96.7) Villous adenoma 3 (27.3) 7 (3.2) Dysplasia Low grade 10 (90.9) 214 (100.0) High grade 1 (9.1) 0 (0.0) Values are presented as mean±sd, n, or n (%). 환자중가족력이있는환자 11명을환자군으로설정하고, 가족력이없는환자중환자군과동일한연령대와성별의 11명을대조군으로선별하여대장선종의임상적특징및면역조직화학발현을비교하였다. 먼저짝지은두군의연령, 성별, BMI, 폴립의개수, 크기, 조직학적형태, 이형성의분포를알아보기위해 McNemar 검정및 paired t-test를시행하였고이에따른선종에서의면역조직화학발현의차이를비교하기위해 generalized estimating equation 분석기법을실시하였다. 결 Table 3. Characteristics of Colonic Adenoma according to Family History of Colorectal Cancer Yes (n=36) 과 1. 대장암의가족력과대장선종발생과의상관관계 대장내시경을시행받은환자총 1,123명중 371명에서대장폴립이발견되었고이중 225명이대장선종으로진단되었으며비선종성폴립환자중 128명은과증식성폴립, 18명은염증성폴립으로진단되었다. 대장폴립및선종의유병률은각각 33.1%, 20.1% 로기존의연구와유사한결과를보여주었다. 대장내시경을시행받은환자총 1,123명중대장암의가족력이있는경우대장선종발생이의미있게증가하였다 (p=0.029) (Table 1). 2. 대장암의가족력에따른대장선종환자의임상적특징 대장선종으로진단된 225명을대장암가족력이있는 11명과나머지 214명의두군으로나누어연령, 성별, BMI, 폴립의개수및크기, 조직학적형태, 이형성과의상관관계를분석한결과대장암가족력이있는군은평균연령이낮았고융모형및고등급이형성선종이발생할확률이높았다 (Table 2). Family history of colorectal cancer No (n=40) Polyp size (mm) <5 12 (33.33) 17 (42.5) 5 and <10 17 (47.22) 12 (30.0) 10 7 (19.44) 11 (27.5) Histology Tubular adenoma 29 (80.56) 35 (87.5) Villous adenoma 7 (19.44) 5 (12.5) Dysplasia Low grade 35 (97.22) 40 (100.0) High grade 1 (2.78) 0 (0.0) p-value a a >0.050 b Values are presented as n (%). a Analyzed by generalized estimating equation, b analyzed by penalized maximum likelihood. The Korean Journal of Gastroenterology

Choi MY, et al. The Effects of Family History of Colorectal Cancer on the Colorectal Adenoma 39 Fig. 1. Immunohistochemical expression of Bax in patient with family history of colorectal cancer.

Immunohistochemical expression of Bax in patient without family history of colorectal cancer. The picture showed higher expression than those of patient group (H&E, 100).

4 Choi MY, et al. The Effects of Family History of Colorectal Cancer on the Colorectal Adenoma 39 Fig. 1. Immunohistochemical expression of Bax in patient with family history of colorectal cancer. The picture showed lower expression than those of control group (H&E, 100). Bax, Bcl-2-associated X protein. Fig. 2. Immunohistochemical expression of Bax in patient without family history of colorectal cancer. The picture showed higher expression than those of patient group (H&E, 100). Bax, Bcl-2-associated X protein. Table 4. Immunoexpressions of β-catenin, Bax, Bcl-2, NF-κB p65, p-akt of Colonic Adenoma according to Family History of Colorectal Cancer Patient group (n=36) Control group (n=40) p-value a β-catenin Positive 32 (88.9) 33 (82.5) Negative 4 (11.1) 7 (17.5) Bax High 28 (77.8) 38 (95.0) Low 8 (22.2) 2 (5.0) Bcl 2 High 22 (61.1) 25 (62.5) Low 14 (38.9) 20 (50.0) NF-κB p65 Positive 18 (50.0) 20 (50.0) Negative 18 (50.0) 20 (50.0) p-akt High 30 (83.3) 36 (90.0) Low 6 (16.7) 4 (10.0) Values are presented as n (%). Bax, Bcl-2-associated X protein; NF-κB p65, nuclear factor kappa B p65; p-akt, phosphorylated AKT. a Analyzed by generalized estimating equation. 3. 대장선종조직에서신호전달인자발현에대한면역조직화학분석 대장선종으로진단된 225명중대장암의가족력이있는 11 명의선종은 36개, 이와짝지은대장암의가족력이없는 11명의선종은 40개였다. 두군간의폴립의크기와조직학적형태및이형성을폴립단위로분석한결과통계적으로유의한변수는없었다 (Table 3). 면역조직화학분석에서 Bax의발현은환자군에서낮게발현되었으며 (Figs. 1, 2) (p=0.046), 다른항체의발현은두군의차이가없었다 (Table 4). 고찰 이번연구에서대장암의가족력이있는경우대장선종의발생연령이낮았으며조직학적으로진행성선종이발생할가능성이높은것으로나타났다. 대장암의가족력은대장암발생의중요한위험요소로알려져있는데전체대장암의 5-15% 에서유전적요인이대장암발생의원인이라고한다. 14 대장암의가족력이있는경우대장선종및진행성선종의발생이증가한다는연구들이보고되고있으나, 다른연구들에서는연관성이없어아직명확한결론은내리기어렵다 American Cancer Society에서제안한대장암예방권고안 22 에따르면, 대장암환자의 80% 에서가족력이있으며직계가족 ( 부모, 형제자매, 자녀 ) 에서가족력이있는경우대장암발생위험률이두배로증가하고, 특히젊은연령의대장암가족력이있거나직계가족중대장암환자의수가증가할수록대장암발생률이높아진다. 이번연구에서 225명의대장선종환자를대상으로대장암의가족력이대장선종의발생에어떠한영향을미치는지분석한결과, 대장암의가족력이있는경우대장선종이의미있게증가하였고, 보다젊은연령에서발생하였으며, 융모형및고도이형성증이더많았다. 이러한결과는대장암의가족력이있는경우 50세보다젊은연령에서대장암선별검사가권고되는것을뒷받침해주는결과라하겠다. 한편대장암의발생은많은경우 WNT/Wingless pathway, TGF-β pathway, K-ras pathway, p53 pathway의 4가지신호전달체계의유전적변이에의해유발되며특히대장암의가족력이있는경우 microsatellite instability가증가한다고보고되었다. 23,24 그중세포증식에중요한 β-catenin의이상발현과 NF-κB p65 및 Bcl-2의과발현은대장선종또는대장 Vol. 60 No. 1, July 2012

5 40 최민영등. 대장암의가족력이대장선종발생에미치는영향 암의발생과연관된다고알려져있고, 반면세포사멸을유도하는 Bax의발현은대장암의진행과의연관성이아직명확하지않은상태이다 이번연구는국내외에서처음으로대장암의가족력에따른대장선종조직의 β-catenin, Bax, Bcl-2, NF-κB p65, p-akt의면역조직화학발현을비교하였다. β-catenin, Bcl-2, NF-κB p65, p-akt는가족력에따라면역조직화학발현의차이를보이지않았으며, 이는대장암의가족력이있는선종환자수가 11명이라는비교적적은표본수에서기인한것으로생각된다. 반면 Bax는가족력이있는대장선종군에서발현이감소하였다. 이러한결과는대장암가족력이있는경우대장선종에서세포증식이활성화되는과정에종양증식을억제하는 Bax의기능감소가관여할가능성을보여준다. Phosphatidylinositide 3-kinase/AKT 신호체계의활성화도대장세포의증식에필요하다고알려져있는데, 이번연구에서대장암의가족력의유무에따른대장선종에서의 p-akt 발현의유의한차이는없는것으로나타났다. 30 이번연구는국내에서처음으로가족력이대장선종의발생에미치는영향에대해면역조직화학염색을통해분석한연구라는점에서의의가있지만, 몇가지제한점을가지고있다. 첫째, 대장암의가족력이있는선종환자수가 11명으로통계적제한이있어결과의해석에주의가필요하다. 둘째, 여러유전자에대한면역조직화학염색을시행하였으나이에대한단백발현이나 messenger RNA 발현등을확인하지못하였고, 정상조직에서의발현정도를확인하지못했다. 이는후향적연구의한계로서향후이에대한대규모전향적연구가필요할것으로생각한다. 이번연구에서는대장암가족력이있는경우대장선종의발생이증가하였으며보다젊은연령에서발생하였고, 조직학적으로진행성선종일가능성이높은것으로나타났다. 향후대장암혹은대장선종의가족력이이들종양의발생과진행에미치는영향및이과정에관여하는세포신호전달인자들의발현양상에대한전향적인추가연구가필요할것으로생각한다. 요약 목적 : 대부분의대장암은대장선종에서발생하는것으로알려져있으며, 대장선종의조기발견이대장암의중요한예방법으로인정되고있는데아직까지국내에서는대장암의가족력이대장선종의발생과어떠한연관성이있는지명확하게밝혀진바가없다. 이에이번연구에서는대장암의가족력이대장선종의발생에어떠한영향을미치는지알아보고, 대장암가족력유무에따른대장선종의 β-catenin, Bax, Bcl-2, NF-κB p65, p-akt의발현을면역조직화학염색을통해비 교하고자하였다. 대상및방법 : 2009년 3월부터 2010년 9월까지대장선종으로진단된 225명을대상으로대장암의가족력에따른선종의크기, 개수및조직학적소견등을비교하였다. 그리고대장선종환자중에서대장암의가족력이있는 11명과성별과연령대가동일하면서가족력이없는 11명의대조군을선택하여 Bcl-2, Bax, p-akt, NF-κB p65, β-catenin의면역조직화학염색발현을비교하였다. 결과 : 대장선종의발생률은대장암가족력이있는경우에유의하게증가하였다 (p=0.029). 가족력이있는대장선종환자는평균연령이낮았으며 (49세 vs. 55.9세, p=0.023) 융모성선종과고등급이형성선종이더많았다 (27.3% vs. 3.2%, 9.1% vs. 0%, p=0.001). Bax 발현은가족력이있는경우에감소하였다 (p=0.046). 결론 : 이번연구는대장암의가족력이있는경우보다젊은연령에서선종의발생이증가하고진행성선종발생이증가할수있음을보여준다. 또한대장암의가족력이있는경우종양억제유전자인 Bax 발현이더낮았는데이는종양억제유전자의발현억제를통해대장선종에서의세포증식이보다촉진될가능성을시사한다. 따라서대장암의가족력이있는경우더이른나이에대장내시경선별검사를시행하는것이바람직하다고생각한다. 색인단어 : 대장신생물 ; 대장선종 ; 대장암의가족력 ; Bcl-2- associated X protein REFERENCES 1. Cancer facts and figures 2010 in the Republic of Korea. [Internet]. Goyang (Korea): National Cancer Center [cited ]. Available from: icsfiles/afieldfile/2010/07/21/cancer_fact_figures_2010_english.pdf. 2. Jackman RJ, Mayo CW. The adenoma-carcinoma sequence in cancer of the colon. Surg Gynecol Obstet 1951;93: Bond JH. Polyp guideline: diagnosis, treatment, and surveillance for patients with colorectal polyps. Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 2000;95: Karin M. NF-kappaB and cancer: mechanisms and targets. Mol Carcinog 2006;45: Moon KM, Park YJ, Kim HS, et al. Correlation of beta-catenin and p53 protein expression with clinico-pathologic characteristics of colorectal Cancer. J Korean Soc Coloproctol 2002;18: Behrens J, Jerchow BA, Würtele M, et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 1998;280: Yu LL, Yu HG, Yu JP, Luo HS, Xu XM, Li JH. Nuclear factor-kappab p65 (RelA) transcription factor is constitutively activated in hu- The Korean Journal of Gastroenterology

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Jkbcs016(92-97).hwp

Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean