원저 Lab Med Online Vol. 6, No. 1: 25-30, January 진단면역학 B 세포림프종의임상적악성도표지자로서혈청 Thymidine Kinase 1 의유용성 Use

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1,3 홍영준 1,3 홍석일 1,3 장윤환 1,3 Heyjin Kim, M.D.

1 원저 Lab Med Online Vol. 6, No. 1: 25-30, January 2016 진단면역학 B 세포림프종의임상적악성도표지자로서혈청 Thymidine Kinase 1 의유용성 Usefulness of Serum Thymidine Kinase 1 as a Biomarker for Aggressive Clinical Behavior in B-cell Lymphoma 김혜진 1 강혜진 2 이진경 1,3 홍영준 1,3 홍석일 1,3 장윤환 1,3 Heyjin Kim, M.D. 1, Hye Jin Kang, M.D. 2, Jin Kyung Lee, M.D. 1,3, Young Jun Hong, M.D. 1,3, Seok-Il Hong, M.D. 1,3, Yoon Hwan Chang, M.D. 1,3 한국원자력의학원원자력병원진단검사의학과 1 내과 2 과학기술연합대학원대학교방사선종양의과학 3 Department of Laboratory Medicine 1, Division of Hematology/Oncology, Department of Internal Medicine 2, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Seoul; Radiological & Medico-Oncological Sciences 3, University of Science and Technology, Daejeon, Korea Background: The cell cycle-dependent enzyme thymidine kinase 1 (TK1) is known to increase during cancer cell proliferation and has been reported as a prognostic marker for various hematologic malignancies and solid tumors. This study aimed to determine the reference interval in Korean healthy controls and to evaluate the usefulness of TK1 as a biomarker for aggressive clinical behavior in B-cell lymphoma patients. Methods: We enrolled 72 previously untreated patients with B-cell lymphoma and 143 healthy controls. Serum TK1 levels were measured by chemiluminescence immunoassay (Liaison, DiaSorin, USA). We established the reference intervals in healthy controls. The diagnostic performance of serum TK1 was studied using receiver operating characteristic (ROC) analysis, and the correlation between the cutoff level for serum TK1 and clinical characteristics of B-cell lymphoma was evaluated. Results: The reference range (95th percentile) of serum TK1 in healthy controls was U/L. There was a clear difference in TK1 levels between patients with B-cell lymphoma and healthy controls (40.6±68.5 vs. 11.8±4.4 U/L, P <0.001). The area under the curve of serum TK1 for the diagnosis of B-cell lymphoma was 0.73 (cutoff, 15.2 U/L; sensitivity, 59.7%; specificity, 83.2%). An increased TK1 level ( 15.2 U/L) correlated with the advanced clinical stage (P <0.001), bone marrow involvement (P =0.013), international prognostic index score (P =0.001), lactate dehydrogenase level (P =0.001), low Hb level (<12 g/dl) (P =0.028), and lymphocyte count (P =0.023). Conclusions: The serum TK1 level could serve as a useful biomarker for aggressive clinical behavior in B-cell lymphoma patients. Key Words: Thymidine kinase 1, B-cell lymphoma, Serum biomarker 서론 악성종양의발생과진행은주로세포증식과세포주기조절의 Corresponding author: Yoon Hwan Chang Department of Laboratory Medicine, Korea Cancer Center Hospital, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea Tel: , Fax: , cyhlabo@kcch.re.kr Received: November 5, 2014 Revision received: June 17, 2015 Accepted: July 28, 2015 This article is available from , Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 기능이상에의한것으로알려져있다. Thymidine kinase (TK) 는세포주기의중요한조절인자중의하나로서, TK1과 TK2 두가지의동위효소가있다. 이중에서 TK1은세포분열이예상될때만세포질에존재하는세포주기의존성 (cell cycle-dependent) 을보이며, DNA 합성과복구및세포증식에관여하는것으로알려져있다 [1-3]. 1980년대이후로악성림프종을진단하는데있어서처음으로 TK1의임상적유용성이발표된이래다수의논문에서급성백혈병, 림프종과같은혈액종양과다양한고형암에서진단또는치료후모니터링과예후예측에중요한표지자로보고되어왔다 [3-13]. 하지만, 당시에 TK1은방사성동위원소를이용한검사법이주종을이루었기때문에진단검사의학과검사실에서는널리사용되지못하였다. 최근화학발광면역측정법 (chemiluminescence immunoassay, CLIA) 을이용하여자동화장비에서측정이가능해짐 eissn

2 으로써다시종양표지자로서의 TK1에대한임상연구가활발히진행되고있다. 성숙B세포종양의대부분을차지하는림프종은주로병리학적조직검사와영상검사및골수검사에의해진단및병기결정이이루어진다. 림프종에대한국제예후지표 (international prognosis index, IPI) 에는연령, 수행도 (performance status), 임상병기, 림프절외병변의개수, 젖산탈수소효소 (lactate dehydrogenase, LD) 활성도가포함된다. 따라서, B세포림프종과관련하여일상검사 (routine test) 로활용되는검사종목들로는 LD, β2-microglobulin, 혈청유리형면역글로불린경쇄 (free immunoglobulin light chain) 등이있고, 기타예후인자로서종양부하량, 세포유전자이상, BCL-2 단백표현, p53 유전자변이등이있다 [14]. B세포림프종의진단및모니터링과정중영상검사로확인하기어려운아형들이있는데, 이러한아형들은상대적으로분열지수가낮고증상의진행이빠르지않으며침습적인형태로진행하는것이특징이다. 이러한 B세포림프종아형의조기발견및예측의중요성이부각되고 rituximab 과같은표적치료제의도입이후광범위B형대세포림프종 (diffuse large B-cell lymphoma, DLBCL) 환자의예후가많이향상됨에따라기존예후인자외의부가적예후인자의발굴이필요하게되었다. 본연구에서는한국인에서화학발광면역측정법을이용한혈청 TK1 정량분석을통하여건강인의혈청 TK1 참고치를설정하고자하였다. 또한병기결정을위해골수검사를시행한 B세포림프종환자를대상으로다양한임상지표들과의상관성을비교하고, 임상적악성도표지자로서혈청 TK1 검사의유용성을평가하고자하였다. 대상및방법 Table 1. Baseline characteristics of healthy controls (N=143) and patients with B-cell lymphoma (N=72) Variables Age (yr) Sex 2. 측정방법 B 세포림프종환자와건강대조군의혈청검체에서화학발광면역 측정법으로혈청 TK1 농도의정량값이측정되었고, 모든과정은 제조사의프로토콜에따라시행되었다 (Liaison, DiaSorin, Stillwater, MN, USA). B-cell lymphoma patients (%) Healthy controls (%) Median Range Male 36 (50) 85 (59) Female 36 (50) 58 (41) Ann Arbor stage I 27 (38) II 18 (25) III 5 (7) IV 22 (31) Bone marrow involvement With involvement 11 (15) Without involvement 61 (85) Histology DLBCL 54 (75) MALT lymphoma 11 (15) Follicular lymphoma 3 (4) Others* 4 (6) *Include small lymphocytic lymphoma, splenic B cell lymphoma, DLBCL associated with low-grade MALT lymphoma, and pediatric nodal marginal zone lymphoma. Abbreviations: DLBCL, diffuse large B-cell lymphoma; MALT lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. 1. 대상 2008년 10월부터 2013년 5월까지한국원자력의학원원자력병원에서 B세포림프종을진단받고골수검사를시행한환자들중한국원자력의학원국가방사선혈액자원은행에입고된 72명의환자검체를대상으로하였다. 모든검체는항암화학요법이나방사선요법등의치료이전에초기진단및병기설정을위한골수검사시행시후향적으로수집된혈청검체였다. 총 72명의환자 ( 남자 36명, 여자 36명 ) 중에광범위B형대세포림프종이 54명으로가장많았다 (Table 1). 또한, 건강대조군 143명 (20세이상 ) 의혈청검체는한국원자력의학원국가방사선혈액자원은행에서 43검체, 경상대학교병원인체자원단위은행에서 100검체를각각분양받았다. 본연구는한국원자력의학원기관생명윤리위원회의심의를통과하였다. 3. TK1의참고범위의설정및 B세포림프종감별의 TK1 기준치설정건강대조군의참고범위를설정하기위해전체대상, 성별, 연령군별로나누어분석하였을때비정규분포를이루었으므로측정된혈청 TK1은 95 percentile의참고구간을설정하였다. 또한, 전체 215명의혈청검체 (B세포림프종환자군 72명, 건강대조군 143명 ) 의혈청 TK1 수치를이용하여 Receiver Operating Characteristic (ROC) 곡선분석을시행하였다. 4. 통계학적분석정규분포의확인에는 Komogorov-Smironov test, 자료는평균값 ± 표준편차혹은중앙값 ( 범위 ) 으로나타내었다. TK1 수치에따른비교대상군간연속변수의비교는 Student t-test나 Mann- Whitney U-test를사용하였고, 빈도비교는 chi-square test와 26

3 Fisher s exact test를이용하였다. B세포림프종의진단을위한건강대조군과의혈청 TK1 수치의감별력을평가하기위해 ROC 곡선분석을시행하여기준치를설정하였으며민감도, 특이도, 곡선하면적 (area under curve, AUC) 을구하였다. P값이 0.05 미만인것을통계적으로유의하다고판단하였고, 통계분석에는 SPSS (version 19.0, IBM, Armonk, NY, USA) 를사용하였다. 결과 1. 참고범위 143명의건강대조군 ( 남성 85명, 여성 58명 ) 이참고범위설정에포함되었으며, 나이의중앙값은 45세 (28-79세) 였다. 혈청 TK1의평균은성별과연령에따른유의한차이를보이지않았다 (P = 0.119, P = 0.707). 전체건강대조군의혈청 TK1의 95 percentile에따른참고범위는 U/L였다. 2. 건강대조군과 B세포림프종진단시의환자혈청 TK1 수치의비교 B세포림프종과건강대조군의혈청 TK1 수치의평균 ± 표준편차는각각 40.6±68.5 U/L ( 범위 : ) 와 11.8±4.4 U/L ( 범위 : ) 로나타나두군간에유의한차이를보였다 (P <0.001) (Fig. 1). 이결과를이용하여 ROC 분석을한결과 B세포림프종환자를선별할수있는혈청 TK1 기준치로 15.2 U/L를설정하였다 ( 민감도 59.7%, 특이도 83.2%, AUC 0.73) (Fig. 2). 3. 혈청 TK1 수치와임상적및검사적특징의연관성혈청 TK1 기준치 (15.2 U/L) 에의해나눈두그룹에서혈청 TK1 의기준치이상 ( 15.2 U/L) 은병기, 골수침범, IPI 점수, LD 수치, 낮은 Hb 값 (<12 g/dl), 림프구수와상관성을보였지만, 나이, 성별, 병리학적 B세포림프종아형, 전신증상의유무, 생존기간, 생존유무, 염색체이상의유무, 백혈구수, 혈소판수에서는유의한차이가관찰되지않았다 (Table 2). 또한, B세포림프종환자에서일상검사로활용되는가장보편적인예후지표인자중의하나인 LD치와혈청 TK1치에서유의한상관성이확인되었다 (Pearson s correlation test; N= 69, R = 0.704, P <0.001). 두그룹간에 LD 치에서유의한차이가있었지만 (P = 0.001) β 2-microglobulin과 C-반응단백 (C-reactive protein, CRP) 에서는유의한차이가없었다 (Table 2). 4. 혈청 TK1 수치와생존율의연관성 2년미만의짧은관찰기간으로인해중앙전체생존기간은설정할수없었으며혈청 TK1 수치에의해나눈두그룹간의비교에서생존기간및생존유무의차이를확인할수없었다 (P = and P = 0.200) (Table 2). 고찰혈청 TK1은 DNA의합성과수선에관여하는피리미딘구제경로 (salvage pathway) 의한효소이다. TK1의활성도는휴지기의세포에서는아주낮거나존재하지않고, G1 후기에서시작하여 S기에 Level of serum TK1 (U/L) * * * Sensitivity AUC=0.73 Healthy controls (N=143) B-cell lymphoma patients (N=72) Fig. 1. Comparison of serum thymidine kinase 1 (TK1) levels between healthy controls and patients with B-cell lymphoma. The upper and lower ends of the boxes and the box inner lines correspond to the 3rd and 1st quartiles and median values, respectively. Error bars denote minimum and maximum values, and circles and stars indicate outlier values Specificity Fig. 2. Receiver operating characteristic (ROC) curve of serum thymidine kinase 1 (TK1) levels in patients with B-cell lymphoma. The area under the curve (AUC) of serum TK1 for the diagnosis of B-cell lymphoma was 0.73 (cutoff, 15.2 U/L) with its 95% confidence interval. 27

4 Table 2. Correlation between serum thymidine kinase 1 (TK1) levels and clinical characteristics of 72 patients with B-cell lymphoma Characteristics TK U/L (N=49) TK1 <15.2 U/L (N=23) P value Age 59.4± ± Sex Male Female Clinical stage I II 11 7 III 5 0 IV 20 2 Limited (I+II) <0.001 Advanced (III+IV) 26 2 BM involvement With involvement Without involvement Histologic type DLBCL MALT 5 6 Follicular 2 1 Others* 3 1 IPI score Low (0+1+2) High (3+4) 13 1 Systemic symptoms Absent Present 7 1 Survival duration (day) 829.3± ,014.0± Survival state Death 12 2 Survival LD (U/L) (N=69) 630.7± ± Chromosomal aberration (N=64) Normal karyotype Abnormal karyotype 4 0 β 2-Microglobulin (g/l) 2.2±0.9 (N=14) 1.1±0.5 (N=6) CRP (mg/dl) 3.0±2.5 (N=22) 2.8±1.8 (N=3) Hb level (g/dl) Low Hb (<12 g/dl) 24 5 Normal Hb ( 12 g/dl) WBCs ( 10 9 /L) 7.00± ± Lymphocytes ( 10 9 /L) 1.54± ± Platelets ( 10 9 /L) 261 ± ± *Include small lymphocytic lymphoma, splenic B cell lymphoma, DLBCL associated with low-grade MALT lymphoma, and pediatric nodal marginal zone lymphoma. Abbreviations: CRP, c-reactive protein; DLBCL, diffuse large B-cell lymphoma; Hb, hemoglobin; IPI, international prognosis index; LD, lactate dehydrogenase; MALT lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue; WBCs, white blood cells. 증가하였다가분열기 (mitosis) 에사라진다 [2, 3]. G2/M기에특이적으로나타나는 TK1 활성의소멸은유비퀴틴-프로테아좀경로에의한것으로여겨지고있다 [15]. 이는 TK1의활성또는농도가세포의증식성과밀접한연관성을가진다는것을의미한다. 정상세포들은 G1기에사멸하는반면대부분의암세포들은세포주기의 G2 기에사멸하기때문에 TK1 농도는암환자에서훨씬더높게측정된다. 현재까지다수의연구에서혈청학적 TK1 활성도또는농도를이용하여혈액종양뿐만아니라다양한고형암에서진단적또는치료반응의표지자로서유용성을보고하였다 [13, 16-18]. B세포림프종은다양한임상적경과와단클론성림프구증식을특징으로하며, 초기림프종의진단시병기결정및치료에따른예후예측이필요하다. 현재 B세포림프종환자들의치료제의개발로생존율이많이향상되었지만, 관찰기간동안이용할수있는혈청표지자가제한적이다. 이전대부분의연구에서혈청 TK1 활성도 ( 또는농도 ) 의측정은방사효소측정법 (radio-enzymatic assay, REA) 또는방사수용체측정법 (radio-receptor assay, RRA) 을사용하였고, B세포림프종환자에서병기설정및치료반응에대한표지자로서 TK1 활성도 ( 또는농도 ) 의유용성을제시하였다 [4, 6, 7]. 하지만, 그러한검사법들은방사성동위원소의이용에따른고비용, 짧은유효기간, 인체유해성, 상대적으로장시간의검사시간소요등과같은검사방법의제한점으로인해국내에서임상검사로서의유용성은아직까지연구되지않았다. 본연구에서는화학발광면역측정법으로가능해진혈청 TK1 정량측정을진단검사의학과검사실에도입하기위해한국인에서의참고치설정및 B세포림프종환자군에서의임상적악성도표지자로서의유용성평가를시행하였다. 한국인에서의혈청 TK1의참고범위는 U/L로, 제조사가제시한참고치 ( U/L) 보다더높게측정되었다. 그이유로는민족적차이, 생활양식차이등을생각해볼수있겠으나, 최근 Szánthó E 등이발표한연구에서동일한검사방법을사용하여암, 대사성질환, 염증성질환환자를제외한건강인의참고치를설정한결과, 본연구와유사하게제조사가제공한참고치보다훨씬높은것으로관찰되었다 [19]. 이미보고된여러논문과마찬가지로본연구에서 B세포림프종환자의혈청 TK1 수치의평균은건강인보다유의하게높았다. 또한, 건강인과 B세포림프종환자의선별을위해설정한혈청 TK1의기준치와 B세포림프종관련인자들과의상관성을조사하였더니병기, 골수침범, IPI 점수, LD 수치, 낮은 Hb (<12 g/dl), 림프구수와상관성을볼수있었다. 이와같은결과로부터 B세포림프종의임상적악성도표지자로서혈청 TK1의유용성을확인할수있었다. 많은암표지자는한가지암에만특이적이지는않다. 1980년대이후로혈액종양에서의종양성장관련표지자 (tumor-growth-re- 28

5 lated marker) 로서의 TK1의가치가보고되어왔고, 현재혈청 TK1 은특정암종과관련없이조기암진행의표지자로서의가능성도제시되고있다 [20, 21]. 특히, 영상검사에서잘관찰되지않는병변을가진환자나영상검사에대한순응도가떨어지는환자의일상검사에서보완적표지자로유용하게사용될수있을것이다 [12]. 본연구의제한점으로는첫째, 후향적연구라는특성상건강대조군에서혈청 TK1 수치의일시적증가에영향을미칠수있는급성질환 ( 감염, 염증 ) 또는생리학적변화 ( 수혈, 수술, 월경 ) 등의존재여부에대한조사가이루어지지않았다는점을들수있다. 둘째, 전체 B세포림프종환자들중높은병기의환자수, 림프종의골수침범을나타낸환자수가상대적으로적었다는점이다. 추후연구에서더많은환자수와함께 TK1 값의상관성조사가필요하다. 또한, B세포림프종환자에서혈청 TK1의추적검사가이루어지지않아치료전후의모니터링기간동안의혈청 TK1의유용성평가가이루어지지않았고, 관찰기간이 2년미만으로짧아 2년간전체생존율과 TK1 수치의상관성을구할수없었다는점도제한점이다. 하지만화학발광면역측정법을이용한국내최초의연구이고한국인에게적용가능한정상참고치를설정하였다는점에서그의의가크다고할수있겠다. TK1과 B세포림프종환자의생존율을연구한일부논문에서혈청 TK1 수치가높은환자들에서생존율이의미있게감소하였다고보고하고있다 [9, 18]. 국내 B세포림프종환자에서 TK1 수치가임상적악성도뿐만아니라예후관련표지자로서도유용하게사용되기위해서는향후장기간의추적조사가필요할것으로생각된다. 결론적으로본연구결과 B세포림프종환자에서화학발광면역측정법을이용한혈청 TK1 정량측정이환자의병기와골수침범등과관련된임상적악성도표지자로서의유용함을확인할수있었다. 또한, 앞으로다양한혈액종양및고형암환자에서도유용한암표지자검사로사용될수있을것으로생각된다. 요약 배경 : Thymidine kinase 1 (TK1) 은세포주기의중요한조절효소로암세포의증식시에증가하는것으로알려져있으며, 현재까지혈액종양과다양한고형암에서진단또는치료후모니터링과예후예측에중요한표지자로보고되고있다. 본연구에서는한국인에서혈청 TK1 정량분석을통하여건강인의혈청 TK1 참고치를설정하고자하였으며 B세포림프종환자를대상으로임상적악성도표지자로서혈청 TK1 검사의유용성을평가하고자하였다. 방법 : 72명의 B세포림프종환자와 143명의건강대조군의혈청검체에서화학발광면역측정법으로혈청 TK1 농도를측정하였다. 건강대조군에서혈청 TK1의참고치를설정하였고, 환자군과건강대조 군에서측정된혈청 TK1 결과를이용해 ROC 분석을통한기준치를구하여상대적으로높은혈청 TK1 정량값과 B세포림프종의임상지표들과의상관성을비교하였다. 결과 : 전체건강대조군의혈청 TK1의 95 percentile에따른참고범위는 U/L였다. B세포림프종환자군과건강대조군의혈청 TK1 수치비교에서평균 ± 표준편차는각각 40.6±68.5 U/L와 11.8±4.4 U/L로나타났으며두그룹간에유의한차이를보였다 (P <0.001). ROC 분석후, 혈청 TK1 수치 15.2 U/L를이용하였을때민감도 59.7%, 특이도 83.2%, AUC 0.73 을보여 B세포림프종환자를선별할수있는기준치로설정하였다. 상대적으로높은혈청 TK1 수치 ( 15.2 U/L) 는병기, 골수침범, IPI 점수, LD 수치, 낮은 Hb (<12 g/dl), 림프구수와상관성이있는것으로나타났다. 결론 : B세포림프종환자에서측정되는혈청 TK1 수치는 B세포림프종의임상적악성도표지자로서유용하게사용될수있을것이다. 감사의글 본연구는 2012년한국원자력의학원방사선중개연구활성화지원사업연구비 ( ) 지원에의하여수행된것입니다. 본연구에사용된인체자원은한국원자력의학원국가방사선혈액자원은행과경상대학교병원인체자원단위은행에서제공받았습니다. REFERENCES 1. Sherley JL and Kelly TJ. Regulation of human thymidine kinase during the cell cycle. J Biol Chem 1988;15;263: Munch-Petersen B. Enzymatic regulation of cytosolic thymidine kinase 1 and mitochondrial thymidine kinase 2: a mini review. Nucleosides Nucleotides Nucleic Acids 2010;29: Aufderklamm S, Todenhöfer T, Gakis G, Kruck S, Hennenlotter J, Stenzl A, et al. Thymidine kinase and cancer monitoring. Cancer Lett 2012;316: Gronowitz JS, Hagberg H, Källander CF, Simonsson B. The use of serum deoxythymidine kinase as a prognostic marker, and in the monitoring of patients with non-hodgkin s lymphoma. Br J Cancer 1983;47: Rehn S, Glimelius B, Sundström C. A comparative study of proliferation-associated parameters in B-cell non-hodgkin lymphoma. Hematol Oncol 1991;9: Hallek M, Emmerich B, Strohmeyer S, Busch R, Reichle A, Senekowitsch R. Activity of serum thymidine kinase in non-hodgkin lym- 29

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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