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1 대한내과학회지 : 제 76 권제 2 호 2009 특집 (Special Review) - 골수이형성증의병태생리, 진단과치료 골수형성이상증후군에서동반되는염색체이상과임상적의미 가톨릭대학교의과대학진단검사의학교실 김명신 Significance of cytogenetics in myelodysplastic syndromes Myungshin Kim, M.D. Department of Laboratory Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis presenting with peripheral cytopenias in combination with a hyperplastic bone marrow and an increased risk of evolution to acute myeloid leukemia (AML). Cytogenetic abnormalities are major determinants in the pathogenesis, diagnosis, and prognosis, and, increasingly, the basis for selection of drugs in individual patients with MDS. Chromosomal abnormalities are detected in 40~70% of patients with de novo MDS and in up to 80-95% of patients with therapy-related MDS. Frequent cytogenetic abnormalities are -5/del (5q), -7/del (7q), +8, del (20q), -Y, del (17p), and del (12p). These chromosome abnormalities are independent prognostic factors predicting overall survival and the likelihood of progression in AML. Continuing studies have been performed and they added and changed the significance of cytogenetic abnormalities. Moreover, molecular cytogenetic method, such as fluorescence in situ hybridization, has enriched the understanding of the biology of MDS and to be complement to the information. The aim of this article is to review the clinical significance of cytogenetic abnormalities in MDS. (Korean J Med 76: , 2009) Key Words: Myelodysplastic syndrome; Cytogenetics; Karyotype 서론골수형성이상증후군 (myelodysplastic syndrome, MDS) 은말초혈액에범혈구감소를나타내며골수의세포충실도증가와무효조혈 (ineffective hematopoiesis) 을특징으로하는클론성조혈모세포질환으로, 하나의질환이라기보다는다양한임상적, 형태적, 생물학적, 유전학적차이를가진여러질환들로구분된다. 현재주로이용되는 MDS의유전학적검사는 1970대부터광범위하게사용된고전적세포유전검사로세포의분열을유도하여적절한분열중기 (metaphase) 단계의염색체를광학현미경을이용해관찰하는방법이다. 이는 MDS의진단및예후판정에중요한역할을하며질환의병태생리를이해하는데도움을준다. MDS 에서만관찰되는특이적인염색체이상은없으며주로 -5/del(5q), -7/del (7q), +8, del (20q), -Y, del (17p), del (12p) 등과같이다른혈액종양에서도동반되는이상들이나타난다. 염색체이상의빈도는 MDS의아형에따라차이를보이는데, 예를들어불응성빈혈 (refractory anemia) 이나환상철적모구불응성빈혈 (refractory anemia with ring sideroblast) 에서는염색체이상의동반빈도가낮고모세포증가불응성빈혈 (refractory anemia with excess blasts) 에서는염색체이상의동반빈도가높다 1-3). MDS에서세포유전검사는그중요성이점점강조되고있으며, 최근형광제자리부합법 (fluorescence in situ hybridization, FISH) 을이용하여분열중기세포뿐아니라간기세포에서도유전학적이상을알수있게됨에따라유전학적변이에관한더많은정보를얻을수있게되었다 4, 5). 본종설에서는 MDS에서의세포유전검사에대해알아보고, 염색체이상의임상적의미를고찰해보고자한다

2 - The Korean Journal of Medicine: Vol. 76, No. 2, Table 1. Frequent chromosomal abnormalities and their frequency in the myelodysplastic syndromes at diagnosis Karyotype de novo MDS therapy-related MDS Abnormal Balanced rearrangements Unbalanced rearrangements Specific abnormalities -5/del (5q) -7/ del7q +8 del (20q) -Y del (17p) complex karyotypes 40-70% 10% 30% 10% 10% 10% 5-8% 5% 3-5% 10-20% 80-95% 4% 12% 40% 50% 90% Figure 1. A schematic of cytogenetic analysis. 세포유전검사세포유전검사는인체의세포를체외에서배양하여분열중기세포를얻어이로부터염색체를분리하고그수적, 형태적변화를관찰하여이상유무를판단하는방법이다. 후천적으로발생하는혈액종양세포의세포유전검사를위한검체에는반드시종양세포가포함되어야하기때문에 MDS에서의세포유전검사에는골수가적절한검체이다. 골수흡인물이잘채취되지않는경우에는골수생검조직을이용하여세포유전검사를할수있다. 골수검체는방부제가포함되지않은헤파린이코팅된주사기에채취하여야하며, 골수채취초기에얻은검체일수록말초혈액에의한희석효과가적으므로더좋은검체이다. 검체는채취당일에즉시검사실로운반하는것이권장되며, 운반시에는실온을유지 하는것이좋다. 검체채취에서부터검사실에서배양하기까지의시간이매우중요하므로, 보존기간이길어지는경우에는배양액을첨가하는것도세포의생존능 (viability) 을높이는데효과적이다. 채취한골수는세포배양과정을거치지않고직접분열중기세포를얻는직접법과배양과정을거치는배양법을적용할수있는데, 직접법은검사시간을단축할수있으나충분한양의분열세포를얻을수없는단점이있으므로대부분의검사실에서는 24~48시간동안세포를배양하는단기배양법을사용하고있다. 배양중방추 (spindle) 의생성을억제하는 colchicines 제제인 Colcemid 등을사용하여세포분열을분열중기에서멈추게하고, 저장용액 (hypotonic KCl) 으로처리하여세포를팽창시켜염색체관찰이용이하도록한다. 팽창된세포를고정용액으로고정하고슬라이드에떨어뜨려건조시킨후적절한염색을실시하여현미경으로염색체의형태를관찰한다 ( 그림 1) 6-9). 일반적으로 20~25개의중기세포를관찰하는데, 두개이상의중기세포에서염색체의추가 ( 과염색체 ) 또는전위 (translocation) 나결손 (deletion) 과같은구조적이상이관찰될때그리고세개이상의중기세포에서염색체소실 (loss) 이관찰될때, 이를클론으로정의하고염색체이상으로판단하여 ISCN 2005에따라결과를기술한다 10). 골수의세포유전검사에서이상이발견되었으나선천성이상과연관이있는특징적인염색체의수적이상, 예를들면 21번삼염색체 (trisomy), 성염색체소실, inv (9) 또는 t (11;22)(q24;q12) 와같은구조적이상이나타나는경우에는이러한염색체이상이 MDS의클론성이상이아니라환자의체질성 (constitutional) 염색체이상일수있다. 이를확인

3 - Myungshin Kim. Significance of cytogenetics in myelodysplastic syndromes - 하기위해서는환자의말초혈액또는피부생검조직에서세포유전검사를시행하며, 만일골수에서발견된것과같은이상이발견되면체질성염색체이상으로판단할수있다. 그러면 MDS 환자에서세포유전검사는언제시행하는것이좋은가? 주치의에따라시기는다양하게결정될수있으나, MDS 진단을위한첫골수검사시에는반드시필요하다는데에는이의가없을것이다. 치료후경과관찰시부가적인염색체이상이나타나면질환의진행을의미하는소견이기때문에 MDS의추적관찰시에도세포유전검사가필요하다. 주치의에따라매번추적골수검사를시행할때마다세포유전검사를동시에시행할수도있고새로운치료를결정할때에만시행할수도있겠으나골수의형태변화보다염색체이상이먼저나타나는경우도있으므로이런사항들을고려하여시기를결정하면되겠다. 조혈모세포이식후세포유전검사는생착판정및공여자- 숙주간키메라증 (donor-host chimerism) 을알아보거나, MDS 의재발을조기에발견하는데도움이된다. 형광제자리부합법 (Fluorescence in situ hybridization) 형광제자리부합법 (fluorescence in situ hybridization, FISH) 검사는혈액종양의염색체이상을검출하는데세포유전검사와함께널리이용되고있다. 이는배양과정을거치지않고세포를직접슬라이드에도말한후여러종류의소식자 (probe) 와반응시켜유전학적변이를관찰하는방법으로, 상품화된다양한소식자가개발되어있다. 특히세포배양이잘되지않는경우나염색체형태가관찰하기에불충분한경우, 배양하지않은간기세포에서도분석할수있다. 통상 24시간이내에결과를알수있으며, 많은수의세포를분석하므로비교적정확한정량분석이가능하다. 또한세포유전검사를위한적절한검체를확보하지못했을때에도골수나말초혈액도말검체, 접촉자국 (touch print) 및파라핀포매조직을이용하여 FISH 검사가가능하다는장점이있다. MDS 환자에서는클론성을확인하기위하여세포유전검사와함께부가적으로 -5/del (5q), -7/del (7q), +8, del (20q) 를 FISH 검사로알아볼수있으며, 경우에따라 11q23 (MLL), 13q14 (RB1), -Y, 17p13.1 (TP53) 을포함시켜검사하기도한다 5, 11, 12). 정상핵형을보인 MDS 환자의 15~20% 에서 FISH 검사를통하여예후와관련된염색체이상을검출하였다는연구보고가있으며 13) 특히세포유전검사에서이상이발견되지않으나염색체결손, 전위, 중복등의이상이동반된 미세한이상 (cryptic abnormality) 은 FISH 검사를통하여검출할수있다 4, 13). 역으로, FISH 검사에서이상이발견된경우에는세포유전검사에서염색체이상을더쉽게발견할수있으며, 이결과를치료후추적검사에도이용할수있다 14, 15). MDS 에서의염색체이상 MDS에서만나타나는특이적인염색체이상은없지만가장흔하게관찰되는이상은유전물질의소실로이는염색체일부의결손또는염색체전체의소실형태로나타난다. 염색체결손은염색체의끝부분에서결손이일어나는말단결손 (terminal deletion) 보다중간부분이소실되는중간결손 (interstitial deletion) 이흔하며, 주로 5, 7, 20번염색체의장완, 17, 12번염색체의단완이소실된다. 이러한염색체결손은단독으로관찰되기도하지만진행된 MDS 환자에서는다른염색체이상과동반된형태로나타나는경우가많다. 염색체소실은염색체 7번, 5번, 그리고성염색체인 Y 염색체에서비교적자주관찰된다. 염색체전체또는일부가추가되는경우는염색체소실보다드물게나타나며염색체 8, 11, 21번에서관찰할수있다. 급성골수성백혈병 (acute myeloid leukemia, AML) 에서흔히나타나는균형전위 (balanced translocation) 는 MDS에서는매우드물다. 그러나염색체의추가또는소실이불균형전위 (unbalanced translocation) 의결과로나타나는경우가있으며, 이는복잡핵형 (complex karyotype) 을동반하는 MDS에서자주관찰되는데대부분염색체 5번또는 7번의이상을포함한다. AML 에서나타나는반복적염색체이상인 t (15;17), t (8;21), inv (16) 등이발견될때에는골수내모세포의비율이 20% 미만이더라도 AML로진단하게된다. 염색체이상의동반빈도는 MDS 아형과모세포비율에따라차이가있으며 de novo MDS 환자의약 40~70%, 항암제나방사선치료등에의해발생한 therapy-related MDS (t-mds) 환자의약 80~95% 로보고에따라다양하다 ( 표 1) 16-19). 흔히나타나는염색체이상은 -5/del (5q), -7/del (7q), +8, del (20q), -Y 등이며 2, 3) 그빈도는인종간차이를보인다 20). 국내에서는 +8, trisomy 1q가외국에비해높게나타나는것으로보고되어있다 21, 22). 다른염색체이상이없이 del (5q) 만동반하고, 저엽거대핵세포 (hypolobated megakaryocytes) 가자주관찰되며혈소판수가정상또는증가되어있는 MDS를 5q 단독결손골수형성이상증후군 (MDS with isolated del (5q)) 으로진단하며 23), 그외에는 MDS 아형에따른특이적인염색체이상은없다

4 - 대한내과학회지 : 제 76 권제 2 호통권제 582 호 Table 2. Cytogenetic prognostic findings in publications with greater than 200 patients examined Authors, year Number of patients Abnormal (%) Good Intermediate Poor Pierre, (43) Normal Complex Morel, (37) Normal, del (5q), -Y, -7/del (7q), del (20q) +8 Complex Greenberg, (40) Normal, del (5q), del (20q), -Y All others Complex, abnormal #7 Solé, (51) Normal, del (5q), del (20q), -Y, del (11q), del (12p) Bernasconi, (60) Normal, del (5q), del (20q), -Y, del (11)(q14q23), del (12p) Haase, ,072 1,080 (51) Normal, +1/+1q, t (1q), del (5q), t (7q), del (9q), del (12p), abnormal #15, t (17q), del (20q), -21, +21, -X, -Y rea 3q, +8, +9, t (11q), del (17p) +8, various single and double defects, del (7)(q31q35) rea 3q, -7, del (7q), +8, del (11q), t (11q23), +19, complex (=3) Complex, -7/del (7q), i (17q) Complex, abnormal #7, rea 3q Complex (>3), t (5q) 형태적으로 MDS가의심되나확실치않은경우에염색체이상은질환의클론성을확인할수있는결과이다. 세계보건기구 (WHO) 는최근의연구성과를더하여 MDS를재분류하였는데말초혈액내모세포 1% 이하, 골수내모세포 5% 미만, 지속적인혈구감소증, 하나이상의세포계열에서명확한형성이상 (dysplasia) 이 10% 미만으로관찰되지만 MDS 의클론성이상으로추정되는염색체이상이동반되어있는경우이를미분류골수형성이상증후군 (Myelodysplastic syndrome, unclassifiable, MDS-U) 으로분류하도록하였다. 그러나몇가지염색체이상의경우형태적이상이동반되지않는다면 MDS의명확한근거가될수없다고하였는데, Y, +8, del (20q) 가이에해당한다. 이러한경우에는추적검사시 MDS의소견인형성이상이나타나는지면밀하게관찰하여진단해야한다 23). MDS 에서의염색체이상과예후와의연관성 MDS에서세포유전검사를통하여 AML로의진행을포함한예후를추정할수있다. 1997년에발표된 International Prognostic Scoring System (IPSS) 에서는 de novo MDS 환자 816명의결과를토대로골수내모세포의비율, 감소된혈구계의수, 염색체이상의종류에따라예후를분류하였다. IPSS에따른예후별염색체이상은세가지로구분할수있는데, 7번염색체의이상, 세가지이상의클론성이상을보이는복잡핵형은나쁜예후인자에해당되고, 정상핵형, del (5q), del (20q), -Y는좋은예후인자에속하며그밖의염색체이상은중등도예후인자에포함된다 24). 이러한 IPSS의염색체이상분류기준은 MDS 환자에서타인간조혈모세포이식성적과도밀접한관련이있다 25). 최근에는 IPSS에서제시한염색체이상외에도 del (11q), del (12p), 3번염색체재배열등여러염색체이상의임상적의의가지속적으로연구되고있다 ( 표 2). MDS 에서흔히나타나는염색체이상과특성 -5/del (5q) -5/del (5q) 는 de novo MDS 의 10~20%, t-mds 에서는 40% 정도에서나타난다. 5q 단독결손골수형성이상증후군은여성에서호발하며 ( 여성 : 남성 =2~3:1) 60~65세에높은발병률을나타낸다. 임상적으로는대적혈구성빈혈 (macrocytic anemia) 과백혈구감소가나타난다. 골수세포충실도는정상또는증가하지만드물게감소하기도한다. 5q13-q31부위가주요결손부위로대부분중간결손의형태를보인다. 적혈구형성이상, 저엽거대핵세포 (hypolobulated megakaryocytes) 또는소거핵구 (micromegakaryocytes) 가관찰된다 ( 그림 2) 26). AML로의진행은드물며예후는좋은것으로알려져있다. 최근보고에따르면 immunomodulatory drug인 lenalidomide 에좋은치료성적을보인다 27). 그러나 del (5q) 가다른염색체이상과동반되어나타나는

$경우는 5q22에-q33 부위가주로결손되며, AML 로진행되는빈도가높고아형도모세포과다무반응빈혈 (Refractory anemia with excess blasts, RAEB) 에속하는경우가많아치료성적도불량하다고알려져있다 28). -7/del (7q) -7/del (7q) 는 de novo MDS 의약 5~10%, t-mds 에서약 50% 정도나타난다.$

5 - 김명신. MDS 의염색체이상과임상적의의 - Figure 2. Partial karyogram (left) and morphology (right) in a bone marrow specimen from a patient with del (5q). 경우는 5q22에-q33 부위가주로결손되며, AML 로진행되는빈도가높고아형도모세포과다무반응빈혈 (Refractory anemia with excess blasts, RAEB) 에속하는경우가많아치료성적도불량하다고알려져있다 28). -7/del (7q) -7/del (7q) 는 de novo MDS 의약 5~10%, t-mds 에서약 50% 정도나타난다. 모든아형의 MDS에서발견되며진행된 MDS 아형에서더많이나타난다. 발병연령은 del (5q) 에비해낮은편이다. 주요결손부위는 7q22와, 보다 telomere 쪽에위치한 7q31-32 그리고 7q36이다 29). 골수에서는모든계열의세포에서형성이상이보이며소거핵구가흔히관찰되고호중구의기능이상에의해감염이흔하게발생한다 2, 24, 30). -7/del(7q) 는항암화학요법에치료반응이좋지않으며관해에도달하더라도조기에재발하는확률이높고생존기간도짧기때문에, 환자의나이와전신상태를고려하여동종조혈모세포이식을시행할수있다. 최근에는메틸화억제제인 5-azacytidine 를사용하여 10개월이상완전관해를유지하는등의치료법이시도되고있다 31) 은다양한혈액종양에서나타나는이상으로 MDS 환자에서는모든아형에서 5~20% 의빈도로다양하게관찰된다 17). 임상적의의는아직불명확하나현재까지는중등도의예후를보이는인자로분류되어있다 24). 질환이진행됨에따라이차적으로발생하는경우가많기때문에치료후에 FISH 또는염색체검사를하여 +8 클론의양을추적하는것이도움이된다. -Y MDS에서 -Y의임상적의의는아직불확실하다. MDS 환자의 10% 정도에서 Y를동반하지만혈액질환이없는노인의 7% 에서도노화현상의하나로 Y가나타난다 32, 33). 따라서 Y 염색체이상만으로 MDS를진단하는것은권장되지않고임상적으로 MDS에합당한소견을보이는환자에서 Y가있는경우에는예후가좋은군으로분류하도록하고있다. Wiktor 들은 Y가전체중기세포의 75% 를넘는경우는정상노화현상이라기보다혈액종양과관련된이상으로생각할수있다고하였다 34). del (20q) del (20q) 는 de novo MDS 의 5%, t-mds 의 7% 정도에서발견되는염색체이상으로주로불응성빈혈이나환상철적모구불응성빈혈에서단독또는다른염색체이상과동반되어나타난다 17). 형태적으로는적모구계와거대핵세포의형성이상을보인다 35). 많은경우 20q 대부분이결손되며, 부분결손의경우 20q11.2-q12 부위를포함한다 36, 37). 단독으로 del (20q) 만동반되었을경우는좋은예후인자에해당되며 AML 로의진행은드물다. del (12p) 12p13 부위를포함하는전위또는결손은다양한혈액종양에서동반되는이상으로 MDS에서는모세포증가불응성빈혈에서발생빈도가높다. IPSS에다르면중등도의예후인자에속하지만최근의보고들은좋은예후인자에포함시키고있다 1, 38)

6 - The Korean Journal of Medicine: Vol. 76, No. 2, del (17p) 결 론 del (17p) 는단순결손뿐아니라 iso (17q) 와같은불균형전위의결과로발생하는데 MDS 환자의 5~7% 정도에서발견되며 17번단완에위치한 TP53 유전자의결손이발병에중요한역할을한다 39, 40). 형태적으로는과립구계의형성이상이특징적인데호중구에서가성펠저- 휴에이상 (pseudo- Pelger-Huet), 작은과립, 세포질내공포 (vacuoles) 를관찰할수있다. 치료에잘반응하지않고짧은생존기간을보인다 41). 정상핵형 30~60% 의 MDS 환자가정상핵형을보인다. 정상핵형을보이는 MDS가모두하나의군에속한다기보다는세포유전검사에서는검출되지않는다양한유전학적이상들을동반한여러질환이여기에포함되었을것으로생각된다. 정상핵형을보이는 MDS는현재까지는좋은예후군으로분류되어있으나 24, 29), 최근에는 MDS에서분자유전학적기법을이용하여점돌연변이 (point mutation) 등의유전학적이상이발견되었고, 임상적의의를밝히기위한연구가활발하게진행되고있어정상핵형을보이는 MDS도보다세분화될것으로예상된다 42, 43). 복잡핵형복잡핵형은세가지이상의염색체이상을동반하는경우를말한다 23). 대부분의복잡핵형은염색체소실, 결손과같은이상을포함하고있으며 5번, 7번염색체또는두염색체모두의이상을동반하는경우가흔하다. 발병연령이대체로높은편으로, 여러단계에거쳐순차적으로축적된유전적불안정성 (genetic instability) 을반영하는현상으로생각된다 29, 44). 항암화학요법에는잘반응하지않고동종조혈모세포이식이유일한치료법이지만최근에는새롭게개발된약제들의사용이시도되고있다 2, 14, 45). 클론성진화 (Clonal evolution) 클론성진화는진단시에는정상핵형을보였던환자에서추적검사시에염색체이상이나타났다든지, 단독염색체이상을가지고있었던환자에서기존의염색체이상과함께부가적인이상을동반하는새로운클론이관찰되는경우를말한다. 특히 AML로진행된 MDS 환자에서이러한클론성진화를보이는경우가 60% 정도로높고생존기간은매우짧다 46-48). MDS는형태에의한분류나임상양상뿐아니라유전적변이도매우다양한질환군으로이를이해하고진단하며환자를치료하는데세포유전검사는필수적이라하겠다. 본논문에서는 MDS에서의세포유전검사와흔히동반되는염색체이상의임상적의미를살펴보았다. 현재까지는 IPSS를기초로치료성적과밀접한연관성을보이는염색체이상을분류하고있지만, 최근에도염색체이상과예후와의연관성은꾸준히연구되고있으며빈도는낮으나임상적의의가있는새로운지표들이추가되고있다. 또한다양한치료약제의개발로기존과다른새로운치료방법을시도하고있기때문에기존의예후지표가향후에도그대로적용되지는않을것이다. 앞으로 FISH를포함한다양한분자유전학적기법들의적용을통해염색체이상뿐만아니라돌연변이등유전학적변이의지속적으로발견이예상되며이를통한 MDS의새로운분류도기대해볼수있겠다. 중심단어 : 골수형성이상증후군 ; 세포유전검사 ; 핵형 REFERENCES 1) Solé F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Luño E, Prieto F, Granada I, Hernández JM, Cigudosa JC, Diez JL, Bureo E, Marquès ML, Arranz E, Ríos R, Climent JAM, Vallespí T, Florensa L, Woessner S. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Br J Haematol 108: , ) Solé F, Luño E, Sanzo C, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Cigudosa JC, Millà F, Ribera JM, Bureo E, Martín ML, Arranz E, Florensa L. Identification of novel cytogenetic markers with prognostic significance in a series of 968 patients with primary myelodysplastic syndromes. Haematologica 90: , ) Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, Kundgen A, Lübbert M, Kunzmann R, Giagounidis AAN, Aul C, Trümper L, Krieger O, Stauder R, Müller TH, Wimazal F, Valent P, Fonatsch C, Steidl C. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110: , ) Cherry AM, Brockman SR, Paternoster SF, Hicks GA, Neuberg D, Higgins RR, Bennett JM, Greenberg PL, Miller K, Tallman MS, Rowe J, Dewald GW. Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic

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7.Æ¯Áýb71ÎÀ¯È« š

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