대한진단검사의학회지제 26 권제 1 호 2006 Korean J Lab Med 2006;26:64-9 원저 진단유전학 혈액종양환자에서관찰되는체질성염색체이상의빈도와종류 허정원 정화순 이화여자대학교의과대학진단검사의학교실 Incidence and Types of Consti

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1 대한진단검사의학회지제 26 권제 1 호 2006 Korean J Lab Med 2006;26:64-9 원저 진단유전학 혈액종양환자에서관찰되는체질성염색체이상의빈도와종류 허정원 정화순 이화여자대학교의과대학진단검사의학교실 Incidence and Types of Constitutional Chromosomal Abnormalities in Patients with Hematologic Malignancies Jungwon Huh, M.D. and Whasoon Chung, M.D. Department of Laboratory Medicine, Ewha Womans University, College of Medicine, Seoul, Korea Background : It is important to distinguish between the constitutional and acquired chromosomal abnormality in bone marrow of the patients with the hematologic malignancies, since the constitutional chromosomal abnormality will be continuously observed, even though in remission status of the disease. In this study, we investigated the incidence and types of constitutional chromosomal abnormalities in patients with the hematologic malignancies. Methods : This study included 396 patients with benign hematologic disorders and 634 with hematologic malignancies. The cytogenetic analysis of bone marrow aspirates were performed by direct or/and short term culture (24-48 hours). The constitutional chromosomal abnormality was confirmed by phytohemagglutinin-stimulated 72 hour culture with peripheral blood lymphocytes. Results : The incidence of constitutional chromosomal abnormalities was 2.8% in patients with benign hematologic disorders and 2.4% in patients with hematologic malignancies. Among the patients with constitutional chromosomal abnormalities and hematologic malignancies, 12 were males and 3 females. Eleven patients had an age greater than 20 years. One patient had trisomy 21, 1 reciprocal translocation, 1 robertsonian translocation, 3 sex chromosome aneuploidy and 9 inv(9). Two patients showed both constitutional and acquired chromosomal abnormalities on the same chromosome. The constitutional chromosomal abnormality was continuously observed in remission status of hematologic malignancies. Conclusions : The incidence of the constitutional chromosomal abnormalities was low in patients with hematologic malignancies, but the chromosome study with peripheral blood or skin fibroblasts may be necessary for determining accurate cytogenetic response during follow up. (Korean J Lab Med 2006;26:64-9) Key Words : Constitutional chromosomal abnormality, Bone marrow, Hematologic malignancies 서 론 체질성염색체이상은모든조직의세포에서동일하게존재하 접 수 : 2005년 10월 27일 접수번호 : KJLM1898 수정본접수 : 2006년 1월 25일 게제승인일 : 2006년 1월 25일 교신저자 : 허정원 우 서울시양천구목동 이화여자대학교의과대학부속목동병원진단검사의학과 전화 : , Fax: JungWonH@ewha.ac.kr 는염색체이상으로출생시부터관찰된다. 획득성염색체이상은출생시염색체이상이없었으나, 질환이발생함에따라염색체이상이획득되는것으로, 질환이발생한조직에서만특이적으로관찰된다. 체질성염색체이상유무를확인하고자할때는말초혈액또는피부섬유세포에 phytohaemagglutinin (PHA) 자극제를첨가하여세포배양을해서확인할수있다 [1]. 골수에서관찰된염색체이상이후천적이상이라면 PHA로자극시킨세포배양에서는정상핵형으로관찰되며, 체질성염색체이상인경우는골수에서 64

2 혈액종양환자에서체질성염색체이상의빈도와종류 65 관찰되었던동일한비정상핵형이말초혈액또는피부섬유세포에서도관찰된다. 체질성염색체이상이유전자의소실이나획득이없는균형재배열 (balanced rearrangement) 인경우, 또는대부분이정상세포이고비정상세포가소수존재하는모자이시즘인경우는표현형이정상인경우가많다 [2, 3]. 따라서본인이체질성염색체이상을가지고있는지모르고지내다가혈액종양으로인해골수염색체검사가의뢰되었을때우연히발견되는경우가있다. 혈액종양환자의골수검체에서관찰된염색체이상이체질성염색체이상인지후천적으로획득된염색체이상인지감별하는것이중요한데, 체질성염색체이상이라면혈액종양이관해에도달한시기에도염색체이상이골수에서지속적으로관찰되기때문이다. 또한체질성염색체이상이있는본인과가족들은유전학적상담이필요할수도있다. 국내문헌중혈액종양환자에서체질성염색체이상이관찰되었던몇몇증례보고들이있으나 [4-7], 종합적으로분석한국내문헌은없다. 이에저자들은혈액종양으로의뢰된골수검체에서체질성염색체이상이관찰되는빈도와종류를알아보고자하였다. 액에서는 XY 세포만관찰되었는데, XYY 세포가소수존재하는섞임증 (mosaicism) 을배제하기위해, 성염색체에대한형광동소교잡법을시행하였다. 형광동소교잡법은말초혈액으로 X/Y probe (Vysis, Downer Grove, IL, USA) 를사용하여제조사에서지시한방법대로시행하였다. 간기세포 500개를핵형분석기 (Cytovision, Applied Imaging International Ltd, UK) 로관찰하였으며, XYY 형광신호에대한정상상한치 (cutoff) 는 0% 기준으로판정하였다. 결 1. 양성혈액질환환자에서체질성염색체이상의빈도와종류 396명환자중체질성염색체이상의빈도는 2.8% (11/396) 였으며, 종류는 inv(9) 가 9명, XXY 1명, der(13;14) 1명이었다. 2. 혈액종양환자에서체질성염색체이상의빈도와종류 (Table 1, 2) 과 재료및방법 1. 연구대상 1998년 6월부터 2005년 7월까지골수검체로염색체검사가의뢰되었던 396명의양성혈액질환환자와 634명의혈액종양환자를대상으로하였다. 혈액종양환자는급성백혈병환자 220명, 골수이형성증후군 62명, 만성골수구성백혈병 77명, 만성골수구증식성질환 69명, 다발성골수종 73명, 만성림프구증식성질환 12명, 악성림프종 121명이포함되었다. 혈액종양환자 634명중 15명 (2.4%) 에서체질성염색체이상이관찰되었으며, 종류는 inv(9)(p11q13) 의빈도가가장높았고 (60%), 그다음은성염색체수적이상의빈도가높았다 (20%). 3. 체질성염색체이상을가진혈액종양환자의특징 (Table 3) 1) 성별, 나이혈액종양환자 15명에서체질성염색체이상이관찰되었으며이중 12명은남자, 3명은여자였고 11명은 20세이상이었다. 2. 염색체검사골수의염색체검사는직접법또는세포분열자극제를첨가하지않고24시간내지48시간세포배양후중기세포를관찰하였다. 체질성염색체이상존재여부를확인하기위한말초혈액염색체검사는 PHA가첨가된배지에서 72시간배양후관찰하였다. G-분염법으로염색한후가능한 20개이상의중기세포를관찰하였으며, 염색체핵형표기는 ISCN 1995 (International System for Human Cytogenetic Nomenclature 1995)[8] 에따랐다. 클론성이있는염색체이상은동일한구조적이상또는획득이 2개이상의중기세포에서관찰될때, 또는동일한염색체가 3 개이상의중기세포에서소실된경우로정의하였다. 3. 형광동소교잡법검사 1명환자는골수에서 XY와 XYY 세포가관찰되었고말초혈 2) 체질성염색체있었던환자의추적관찰결과혈액종양이관해에도달했을때도체질성염색체이상은지속적으로관찰되었다 (case 5, 6, 9, 10, 12). Table 1. Incidence of constitutional chromosomal abnormality in patients with hematologic malignancies Disorders % (No.) Overall 2.4 (15/634) Acute leukemia 2.7 (6/220) MDS 3.2 (2/62) CML 3.9 (3/77) MPD 0.0 (0/69) MM 1.4 (1/73) CLPD 8.3 (1/12) ML 1.7 (2/121) Abbreviations: MDS, myelodysplastic syndrome; CML, chronic myelogeneous leukemia; MPD, myeloproliferative disorder; MM, multiple myeloma; CLPD, chronic lymphoproliferative disorder; ML, malignant lymphoma.

3 66 허정원 정화순 3) 체질성이상과후천적이상이동일한염색체에서관찰된환자 (Fig. 1) 1명의급성백혈병환자 (case 2) 에서 2번과 6번염색체에이상이관찰되었는데, PHA 자극제를첨가하여말초혈액염색체검사를시행한결과, 2번과 6번장완의전좌는체질성이상이고, 6번염색체단완에 2번염색체단완이삽입된형태는후천적이상이 Table 2. Incidence of constitutional chromosomal abnormality according to the types of chromosomal aberrations in 15 patients Chromosomal aberrations This study [9]* % (No.) [10] [11] [12] [13] (1) Reciprocal 7 (1) translocation Robertsonian 7 (1) translocation Sex chromosome 20 (3) aneuploidy inv(9) 60 (9) *This study excluded patients with trisomy 21 or inv(9). Abbreviation:, reference. 었다. 또한만성골수구성백혈병환자 (case 8) 에서 inv(9) 가있었던동일한 9번염색체에 t(9;22) 이발생하여 der(9)t(9;22) 염색체모양이전형적인 der(9)t(9;22) 의모양과달랐다. 4) 성염색체수적이상이있었던환자의특징 1명환자 (case 5) 는골수염색체검사에서 47,XYY 세포와 46,XY가모두관찰되었는데, 말초혈액염색체검사를시행한결과는 46,XY 세포만관찰되었다. XYY 세포가소수존재하는섞임증을배제하기위해말초혈액검체에서형광동소교잡법을시행한결과 XYY에해당하는신호가 2.8% 관찰되었다. 고 혈액종양환자에서체질성염색체이상의빈도는 % 로보고되며 [9-13]. 본연구결과는 2.4% 였고, inv(9) 의빈도가가장높았다 (60%)(Table 2). 다른연구결과에서는 inv(9) 의빈도가낮았거나 [10-13], inv(9) 가있었던환자를연구대상에서제외하였으며 [9], trisomy 21의빈도가상대적으로높았다 (Table 2) 찰 Table 3. Characteristics of 15 patients with constitutional chromosomal abnormality No. case Age/ Sex Diagnosis Peripheral blood Karyotype Bone marrow 1 1D/M Acute leukemia 47,XY,+21 47,XY,+21c[20] 2 1M/M Acute leukemia 46,XY,t(2;6)(q37;q23) 46,XY,der(2)t(2;6)(q37;q23)c, der(6)ins(6;2)(p21.3;p13p24)t(2;6)(q37;q23)c[20] 3 66/F MM 45,XX,der(13;14)(q10;q10) 45,XX,der(13;14)(q10;q10)c[20] 4 36/M No BM involvement of ML 47,XXY[88]/48,XXXY[1]/46,XY[11] 47,XXYc[20] 5 47/M MDS 46,XY (FISH, XYY 2.8%) 47,XYYc[4]/46,XY[20] Normocellular (6 Mo) 47,XYYc[2]/46,XY[18] 6 25/M Known CML 47,XYY 47,XYYc,t(9;22)(q34;q11.2)[17]/47,XYYc[3] CR (3 Mo) 47,XYYc[20] 7 24/M Known CML 46,XY,inv(9)(p11q13) 46,XY,inv(9)(p11q13)c,t(9;22)(q34;q11.2)[20] CR (15 Mo) 46,XY,inv(9)(p11q13)c,t(9;22)(q34;q11.2)[4]/46,XY,inv(9) (p11q13)c[16] 8 52/M CML Not tested 46,XY,der(9)inv(9)(p11q13)ct(9;22)(q34;q11.2),der(22)t(9;22)[20] 9 30/F Acute leukemia 46,XX,inv(9)(p11q13) 46,XX,del(7)(q33),t(8;21)(q22;q22),inv(9)(p11q13)c CR (2 Mo) 46,XX,inv(9)(p11q13)c[20] 10 25/F Acute leukemia 46,XX,inv(9)(p11q13) 46,XX,inv(9)(p11q13)c[20] CR (1 Mo) 46,XX,inv(9)(p11q13)c[9] 11 3/M Acute leukemia 46,XY,inv(9)(p11q13) 46,XY,inv(9)(p11q13)c[20] 12 15/M Acute leukemia 46,XY,inv(9)(p11q13) 46,XY,inv(9)(p11q13)c[20] CR (1 Mo) 46,XY,inv(9)(p11q13)c[4] 13 34/M MDS 46,XY,inv(9)(p11q13) 46,XY,inv(9)(p11q13)c,del(20)(q13.1)[12] Persistent (1 yr) 46,XY,inv(9)(p11q13)c,del(20)(q13.1)[25]/47,idem,+8[1]/ 48,idem,+8,+9[2] 14 52/M CLPD 46,XY,inv(9)(p11q13) 46,XY,inv(9)(p11q13)c,t(16;17)(p13.3;q21)[16]/46,XY,inv(9) (p11q13)c[4]/ 15 52/M No BM involvement of ML 46,XY,inv(9)(p11q13) 46,XY,inv(9)(p11q13)c[20] Abbreviations: CR, complete remission; D, days; Mo, months; yr, years; MM, multiple myeloma; ML, malignant lymphoma; MDS, myelodysplastic syndrome; CML, chronic myelogeneous leukemia; CLPD, chronic lymphoproliferative disorder.

혈액종양환자에서체질성염색체이상의빈도와종류 67 1 2 3 4 5 1 2 3 4 5 6 7 8 9 10 11 12 6 7 8 9 10 11 12 13 14 15 16 17 18 13 14 15 16 17 18 19 20 21 22 X Y A 19 20 21 22 X Y B 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

본결과에서 inv(9) 외에다른체질성염색체이상의증례수가너무적어추후연구가필요한것으로생각한다. 혈액종양의발생이체질성염색체이상과연관성이있는지에대한연구들을살펴보면, 다운증후군환자는선천성백혈병과일과성골수구증식증의발생빈도가높았다 [14-17]. 또한클라인펠터증후군은비호치킨림프종의발생과연관성이높은것으로보고하였다 [18, 19].

그러나 trisomy 21 과 XXY 염색체이상을제외하고는혈액종양환자와일반정상집단에서체질성염색체이상의빈도는차이가없다고보고하였으며 [9, 12], 본연구의혈액종양환자와양성혈액질환환자에서도빈도에차이가없었다.

4 혈액종양환자에서체질성염색체이상의빈도와종류 X Y A X Y B X Y C [10-13]. 본연구에서 inv(9) 를가진환자들을제외하면, 체질성염색체이상이관찰되는빈도는혈액종양환자중 0.9% 로다른보고와비슷하였다. 또한혈액종양환자와양성혈액질환환자의체질성염색체이상의빈도 (2.4% vs 2.8%) 는차이가없었으며, 두군에서모두 inv(9) 의빈도가가장높았다. 본결과에서 inv(9) 외에다른체질성염색체이상의증례수가너무적어추후연구가필요한것으로생각한다. 혈액종양의발생이체질성염색체이상과연관성이있는지에대한연구들을살펴보면, 다운증후군환자는선천성백혈병과일과성골수구증식증의발생빈도가높았다 [14-17]. 또한클라인펠터증후군은비호치킨림프종의발생과연관성이높은것으로보고하였다 [18, 19]. 본연구에서도 +21이관찰되었던환자는급성백혈병환자였고 (Table 3, case 1), 47,XXY가관찰되었던환자는비호치킨림프종이있었다 (Table 3, case 4). 그러나 trisomy 21 과 XXY 염색체이상을제외하고는혈액종양환자와일반정상집단에서체질성염색체이상의빈도는차이가없다고보고하였으며 [9, 12], 본연구의혈액종양환자와양성혈액질환환자에서도빈도에차이가없었다. 체질성염색체이상중 47,XYY, der(13;14), inv(9)(p11q13) 와같은이상은표현형에특별한이상을초래하지않지만 [3, 20], 골수에서관찰된염색체이상이체질성인지후천성인지감별하는것은중요하다. 왜냐하면체질성염색체이상은혈액종양이관해 Fig. 1. G-banded karyotype of case 2 (A, B) and case 8 (C). (A) Peripheral blood, showing 46,XY,t(2;6)(q37;q23). (B) Bone marrow, showing 46,XY,der(2)t(2;6)(q37;q23)c,der(6)ins(6;2)(p21.3; p13p24)t(2;6)c. (C) Bone marrow, showing 46,XY,der(9)inv(9) (p11q13)ct(9;22)(q34;q11.2),der(22)t(9;22). 에도달한시기에도골수에서지속적으로관찰되기때문이며세포유전학적관해판정시이를고려해야한다. 본연구에서도관해에도달한혈액종양환자에서체질성염색체이상은지속적으로관찰되었다 (Table 3, case 5, 6, 9, 10, 12). 따라서진단시관찰된염색체이상이체질성염색체이상인지후천적염색체이상인지확인을해야추적관찰시세포유전학적관해여부를정확히판단할수있을것이다. inv(9) 는정상변이형과연관된체질성염색체이상중가장흔하며, 혈액종양과연관된특이적인염색체이상이아니므로, 골수에서 inv(9) 가관찰되었을경우체질성염색체이상일가능성이높다. 또한혈액종양환자에서로버트손전좌가후천적으로발생했던보고가있으나 [21], 비상동염색체로이루어진로버트손전좌는거의대부분이체질성염색체이상이다 [22, 23]. 이와같이 inv(9) 또는로버트손전좌같은염색체이상이골수에서관찰될경우는체질성염색체이상일가능성이높지만, 성염색체의수적이상은체질성인지후천성이지판단하기어렵다. 일반적으로혈액종양에서성염색체의수적이상은단독으로발생하기보다는일차적염색체이상외에성염색체의수적이상이이차적으로동반되는경우가많다. 그러나드물게혈액종양환자에서후천적염색체이상중하나로성염색체의수적이상이단독으로관찰될수도있는것으로보고하였다 [24, 25]. 예를들면 45,X,-X, 47,XY,+X, 47,XY,+Y 등과같이다른염색체이상을동반하지않고성염색

5 68 허정원 정화순 체의수적이상이단독으로혈액종양환자에서관찰될수있다. 따라서 X 염색체가 2개, Y 염색체가 1개관찰될때클라인펠터증후군인지, 아니면 X 염색체가후천성염색체이상중하나로획득된것인지감별하는것이중요하다. 본연구에서성염색체수적이상이있었던환자는 3명이었는데 (Table 3, case 4-6), 그중 2명은성염색체의수적이상이단독으로관찰되었다. 말초혈액염색체검사를통해모두체질성염색체이상임을확인하였다. 2명환자는 XYY 증후군때문에 Y가 2개관찰되었고, 혈액종양이관해에도달한시기에도 Y는계속 2개로관찰되었다 (case 5, 6). 또한체질성염색체이상과후천적염색체이상이동일한염색체에있을경우전형적인염색체이상형태와달라핵형판정과체질성과후천적염색체이상의감별이어려울수있다. 본연구에포함되었던만성골수구성백혈병환자 (Table 3, case 8) 는 inv(9) 가있었던 9번염색체에 t(9;22) 이발생하여전형적인 der(9)t(9; 22) 의모양과달랐다 (Fig. 1). 또한급성백혈병환자 (Table 3, case 2) 에서관찰된염색체이상은백혈병에특이적인염색체이상이아니어서, PHA를첨가하여말초혈액염색체검사를추가로시행하였으며, 동일한염색체위에체질성염색체이상과후천적염색체이상이동시에있음을확인할수있었다 (Fig. 1). 다른문헌에서도 [26, 27], 골수이형성증후군환자의골수에서관찰된염색체이상의절단점 (breakpoint) 이골수이형성증후군에특이적인위치가아니어서, 말초혈액과피부섬유세포염색체검사결과, 체질성이상임을확인할수있었다. 이와같이혈액종양과연관성있는특이적인염색체이상이아닌다른이상이관찰될경우에는체질성염색체이상이동반되었을가능성을고려할필요가있다. 결론적으로혈액종양환자에서체질성염색체이상이관찰되는빈도는낮았지만, 성염색체의수적이상이단독으로관찰될때또는혈액종양과연관된특이적염색체이상이아닌다른이상이관찰될때, 체질성이상과후천적염색체이상을감별하기어려웠다. 체질성염색체이상은관해여부와무관하게지속적으로관찰되므로추적관찰시세포유전학적관해여부를정확히판단하기위해서는말초혈액또는피부섬유세포염색체검사를추가로시행하여체질성과후천성염색체이상을감별하는것이필요하다. 요약배경 : 혈액종양환자의골수검체에서관찰된염색체이상이체질성인지후천적으로획득된이상인지감별하는것은중요하다. 이는체질성염색체이상이있는환자에서는혈액종양의관해시기에도염색체이상이지속적으로관찰되기때문이다. 저자들은혈액종양으로의뢰된골수검체에서체질성염색체이상이관찰되는빈도와종류를알아보고자하였다. 재료및방법 : 연구대상은 396명의양성혈액질환환자와 634명의혈액종양환자를포함하였다. 골수의염색체검사는직접법또는세포분열자극제를첨가하지않고 24시간내지 48시간 세포배양후중기세포를관찰하였다. 말초혈액의염색체검사는 PHA가첨가된배지에서 72시간배양후관찰하였다. 결과 : 체질성염색체이상은양성혈액질환환자에서 2.8% (11/396), 혈액종양환자중 2.4% (15/634) 에서관찰되었다. 체질성염색체이상이관찰되었던혈액종양환자는남자 12명, 여자 3명이었고, 11명환자는 20세이상이었다. 관찰된염색체이상의종류는 +21 1명, 균형전좌 1명, 로버트손전좌 1명, 성염색체수적이상 3명, inv(9) 9명이었다. 또한 2명의환자에서체질성염색체이상이관찰되었던동일한염색체에후천성염색체이상이동시에관찰되었다. 체질성염색체이상을가지고있었던환자는혈액종양이관해에도달했을때도체질성염색체이상이지속적으로관찰되었다결론 : 혈액종양환자에서체질성염색체이상이관찰되는빈도는낮았지만, 체질성염색체이상은관해여부와무관하게지속적으로관찰된다. 따라서추적관찰시세포유전학적관해여부를정확히판단하기위해서말초혈액또는피부섬유세포염색체검사를추가로시행하여체질성과후천성염색체이상을감별하는것이필요하다. 참고문헌 1. Dewald GW, Ketterling RP, et al. eds. Cytogenetic studies in neoplastic hematologic disorders. In: McClatchey KD, ed. Clinical laboratory medicine. 2nd ed. Philadelphia: Lippincott Willimas and Wilkins, 2002: Gardner RJM and Sutherland GR. The origins and consequences of chromosome pathology. In: Gardner RJM and Sutherland GR, eds. Chromosome abnormalities and genetic counselling. 3rd ed. New Work: Oxford University Press, 2004: Van Dyke DL and Wiktor A. Clinical cytogenetics. In: McClatchey KD, ed. Clinical laboratory medicine. 2nd ed. Philadelphia: Lippincott Willimas and Wilkins, 2002: Choi YN, Chun JH, Oh SH, Lyu CJ, Yang CH, Kim KY. The clinical features and prognosis of leukemia in Down syndrome. Korean J Pediatr Hematol-Oncol 2002;9: ( 최예나, 전지현, 오승환, 유철주, 양창현, 김길영. 다운증후군과동반된백혈병환자의예후및임상분석. 대한소아혈액종양학회지 2002;9: ) 5. Kim SE, Kim SH, Kim MY, Lee JN, Lee SY. Transient myeloproliferative disorder with mosaic Down syndrome. A case report. Korean J Hematol 2000;35: ( 김세은, 김상희, 김명유, 이정녀, 이순용. Mosaic Down 증후군에동반된일과성골수증식장애. 대한혈액학회지 2000;35: ) 6. Kye NY, Lee KH, Cha JK, Yoon HS, Song WK. A case of congenital acute megakaryoblastic leukemia with Down syndrome. J Korean Pediatr Soc 1997;40: ( 계난이, 이건희, 차재국, 윤혜선, 송원근.

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7.Æ¯Áýb71ÎÀ¯È« š J KMA Special Issue Myelodysplastic Syndrome June Won Cheong, MD Yoo Hong Min, MD Department of Internal Medicine, Yonsei University College of Medicine E mail : jwcheong70@yumc.yonsei.ac.kr minbrmmd@yumc.yonsei.ac.kr