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1 대한내분비외과학회지 : 제10권제1호 Vol. 10, No. 1, March 2010 종설 여포세포유래갑상선암의유전자이상 서울대학교의과대학외과학교실, 암연구소 이규언ㆍ지현근ㆍ윤여규 Genetic Alterations in Follicular Cell-derived Thyroid Carcinomas Kyu Eun Lee, M.D., Hyun-Keun Chi and Yeo-Kyu Youn, M.D. The molecular approaches to human diseases are receiving greater attention following the completion of the Human Genome Project. Molecular biology techniques are being widely applied to the field of tumor biology, and thyroid carcinomas are not an exception; several genetic alterations have been suggested to play roles in thyroid carcinogenesis and its progression. Malignant tumors arising from thyroid follicular cells can be classified into papillary carcinoma, follicular carcinoma, poorly differentiated carcinoma and anaplastic carcinoma. BRAF mutation, RET/PTC rearrangement and RAS mutation are the suggested molecular causes of papillary thyroid carcinoma (PTC). RAS mutation, PAX8- PPARγrearrangement, PTEN mutation or methylation, and PIK3CA mutation are known to induce follicular thyroid carcinoma (FTC). Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are related to adding p53 or β-catenin gene alterations to those of papillary or follicular carcinomas. The more aggressive genetic alterations are added stepwise as thyroid tumors advance from differentiated PTC or FTC to less differentiated PDTC and finally to ATC. Studying the molecular mechanisms underlying thyroid carcinogenesis may help overcome the limitations of the current diagnostic methods and this may provide more accurate diagnostic and prognostic tools. Furthermore, research at the molecular level is essential for personalized therapies and creating targeted therapies for thyroid carcinomas. (Korean J Endocrine Surg 2010;10:1-11) 책임저자 : 윤여규, 서울시종로구연건동 28 번지 , 서울대학교의과대학외과학교실, 서울대학교의과대학암연구소 Tel: , Fax: ykyoun@plaza.snu.ac.kr 게재승인일 :2010 년 3 월 3 일이논문또는저서는 2009 년정부 ( 교육과학기술부 ) 의재원으로한국연구재단의지원을받아수행된연구임 ( ). Key Words: Genetic alteration, Mutation, Carcinogenesis, Oncogene, Thyroid cancer 중심단어 : 유전자이상, 돌연변이, 발암, 종양유전자, 갑상선암 Department of Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea 서 종양유전자 (oncogene) 에의해종양이발생한다는사실의발견을시작으로질병에대한분자수준에서의접근이시도되어왔다. 특히인간유전체프로젝트 (Human Genome Project) 를통해인간의유전체에담겨있는유전정보를해석하는일이가능해진이후, 질병에대한분자생물학적접근법이각광을받고있다. 악성종양은대부분의선진국에서사망의주된원인을차지하며, 따라서분자생물학적연구가가장활발한분야가종양학이다. 종양의유발원인은다양하지만, 유전정보를담고있는유전자의이상이그원인가운데하나로지목되고있다. 갑상선암의발병기전및진행기전에대해서도다양한유전자이상 (genetic alterations) 이거론되고있는상황이다. 분자생물학적접근법은표면적현상의관찰에의존하는기존방식의한계를개선하여보다정확한진단및예후예측을가능하게할수있다. 또한분자수준에서의선택적억제제등을적용하여보다종양특이적인치료가가능하며, 특히환자맞춤형치료 (personalized therapy) 및표적치료 (targeted therapy) 의적용을위해분자발병기전에대한연구는필수적이다. 갑상선은여포 (follicle) 구조를형성하는여포세포와여포주변부의부여포세포 (paraparafollicular C cell) 로구성된다. 대부분의갑상선암은여포세포에서유래하는데, 분화도에따라유두암 (papillary thyroid carcinoma), 여포암 (follicular thyroid carcinoma), 저분화암 (poorly differentiated thyroid carcinoma), 역형성암 (anaplastic thyroid carcinoma) 으로구분할수있다.(1) 이외에부여포세포에서유래하는수질암 (medullary thyroid carcinoma) 과갑상선으로침윤한림프구의과다증식으로인해갑상선림프종 (thyroid lymphoma) 등이발 론 1

2 2 대한내분비외과학회지 : 제 10 권제 1 호 2010 Fig. 1. Thyroid carcinoma-related signal pathways. Proto-oncogenes and oncogenes are shaded in the diagram. Rectangular figures represent membrane proteins, and round figures cytoplasmic proteins. 생하기도한다. 갑상선암은 RAS-RAF-MEK-ERK로이어지는 MAPK (mitogen-activated protein kinase) 신호전달체계상의유전자이상이발견되는경우가많다. 종종 RET이과발현되거나재조합이일어난경우도 RAS 이하 MAPK/ERK 신호전달체계가활성화된다. 최근들어 PI3K (Phosphoinositide 3-kinase) 신호전달체계의이상도갑상선암의발생에관여함이알려져있다. 본문에서는 MAPK 신호전달체계상의유전자를중심으로갑상선유두암, 여포암, 저분화암, 역형성암등여포세포에서유래한악성종양의유전자이상에대해주로언급하기로한다 (Fig. 1). 본 론 1) 갑상선분화암에서발생하는유전자이상 갑상선유두암 (papillary thyroid cancer) 을유발하는유전자이상은 BRAF 돌연변이, RET/PTC 재조합, RAS 돌연변이등이알려져있다. 이들은각각이암을유발하는별도의분자생물학적기전 (distinct molecular pathway) 인것으로생각되고있으며, 상호배제성 (mutual exclusivity) 이존재한다.(2) 갑상선유두암은발암유전자의체세포점돌연변이로발생하는것 (BRAF, RAS 등 ) 과방사선노출에이은염색체재조합으로발생하는것 (RET/PTC, NTRK1, AKAP9- BRAF 등 ) 의두종류로나눌수있다.(3) 갑상선여포암 (follicular thyroid cancer) 을유발하는유전자이상은 RAS 돌연변이, PAX8-PPARγ 재조합, PTEN 돌연변이및메틸화, PIK3CA 돌연변이등이알려져있다. 유두암과마찬가지로이들유전자이상간에는상호배제성 (mutual exclusivity) 이있다. 여포암 (60 75%)(4-8) 은유두암 (40 50%)(9-11) 에비해결실 (deletion), 역위 (inversion), 전위 (translocation), 중복 (duplication) 등염색체이상의비율이높다. (1) BRAF 돌연변이 : BRAF는아미노산가운데세린및트레오닌을선택적으로인산화시키는효소이다. RAF family 유전자는 1983년마우스에서섬유육종 (fibrosarcoma) 를일으키는 retrovirus에서처음발견되어 RAF (rapidly accelerated fibrosarcoma) 라는이름을얻었다. 이후마우스유전체 (genome) 에서도동일한염기서열 (cellular homologue) 이발견되었으며 A, B, C형의아형 (isoform) 이존재한다고알려져있다.(17) CRAF는또한 RAF-1으로도불리는데, 모든세포에존재한다.(18) BRAF는주로혈액세포, 신경세포, 고환세포에서많이발현하며다양한종류의종양에서돌연변이형태로존재함이발견되어주목을받게되었다.(19) ARAF와 CRAF는 RAS와 SRC에의해서인산화 ( 활성화 ) 되어 MAPK 신호전달체계를활성화하는반면에 BRAF는 SRC 없이도동일하게작용할수있다. 뿐만아니라 BRAF 는 ARAF나 CRAF에비하여 MEK에강하게결합하며신호를전달한다.(20) BRAF 돌연변이는 Sanger Institute의종양유전체프로젝트 (Cancer Genome Project) 를통하여발견되었다. 이프로젝트는인간유전체프로젝트를통해밝혀진 DNA 서열을이용하여대규모스크리닝을수행, 종양에서특이적으로일어나는서열변화를확인하는방식으로진행되었다.(21) 대부분의돌연변이는 BRAF 유전자의 1,799번째핵산에발생하는데, 이경우 BRAF 단백질은 600번째의발린 (valine, V) 이글루타민산 (glutamate, E) 로치환된비정상단백질이되며이를 V600E로표기한다. 초기에는잘못된핵산서열 (NM_ ) 을바탕으로 1,796번째핵산 (V599E) 에돌연변이가있는것으로알려졌으나이후정확한핵산서열 (NT_ ) 이밝혀지면서 1,799번째핵산의돌연변이 (V600E) 로정정되었다.(22) 비정상 BRAF 단백질은항상인산화되어하위신호전달체계를활성화시킨다.(23) 비정상 BRAF 단백질이항상인산화되는기작은 2004년 Wan 등의연구를통해밝혀졌다. 활성화되지않는 BRAF 단백질은인산화도메인에 ATP 결합도메인이항상붙어있는상태로유지되는데 BRAF V600E 돌연변이가발생하면이결합이흐트러져항상인산화되도록작용한다.(24) BRAF의점돌연변이는흑색종 (melanoma) 과갑상선암 (thyroid cancer) 에서높은빈도로발견되며이외에도대장암, 난소암등에서도보고된바있다.(21) 갑상선암은여러타입으로세분화할수있는데 BRAF 돌연변이는특히유두암및유두암유래역형성암에서만발견된다는특징이있다.(25) 갑상선유두암의약 45% 에서발견되는데지역에따라편차를보인다.(26) 한국에서는다른국가에비해높

3 이규언외 : 여포세포유래갑상선암의유전자이상 3 아유두암의 63 83% 에서발견된다.(27,28) 갑상선유두암가운데예후가나쁜키큰세포변이형 (tall cell variant) 유두암에서높은비율로발견되며,(25) 유두암유래역형성암에서도높은빈도로발견되지만여포암에서유래한역형성암에서는발견되지않는다.(29) 갑상선암의악성도를예측하는예후인자는갑상선외침윤 (extrathhyroidal extension), 암병기 (tumor stage), 림프절전이 (lymph node metastasis) 가대표적인데 BRAF 돌연변이는이들인자와상관관계가있음이밝혀져있다.(30) 특히종양단계가 1기나 2기인초기의암에서도 BRAF 돌연변이가존재하면재발률이높아진다는보고가있으며,(30,31) BRAF 돌연변이가존재하는갑상선암은요오드수송에관여하는 NIS (sodium-iodine symporter) 의발현이감소되어방사능요오드치료가어려운경우가많음이알려져있다.(32) BRAF 돌연변이는 RAS 돌연변이나 RET/PTC 염색체재조합과마찬가지로종양발생 (tumor initiation) 에관여한다고생각된다. 전암성색소세포성모반 (premalignant melanocytic nevi) (85%) 과갑상선미세유두암 (17 52%) 에서높은빈도로발견되는사실을그증거로들수있다.(33-35) 세포주실험에서밝혀진바에따르면 BRAF 돌연변이는 DNA 합성을촉진시키지만동시에세포사멸 (apoptosis) 를유발하여세포성장을촉진하는효과는거의없다. 따라서실질적으로는 BRAF 돌연변이로인해생기는유전적불안정성 (genetic instability) 또는후성학적변화 (epigenetic change) 를통해서예후에영향을주는것으로생각된다.(36) BRAF 돌연변이는 TSH (thyroid stimulating hormone) 수용체의발현을감소시킨다는점에서는 RET/PTC와유사하지만, RET/ PTC와는다르게 camp 발현을억제하거나 camp 활성을감소시키지못한다. 그리고 BRAF V600E를마우스에주입하면사람의유두암과유사한종양이발생한다고알려져있다.(23) BRAF V600E 돌연변이발생에미치는환경적요인에대한역학조사결과는추가연구의필요성을시사해준다. 자외선노출은흑색종의유발인자인데, 자외선노출의정도와 BRAF V600E 돌연변이의발생률은상관관계가없는것으로알려져있다.(37) 반면이탈리아에서는화산지형지역의갑상선유두암환자가타지역에비하여 BRAF V600E 돌연변이의빈도가높다는결과를보고하여아직알려지지않은유발인자의존재가능성에대해언급하였다.(38) 최근요오드섭취가 BRAF V600E 돌연변이의발생을유발하는인자일가능성도제시되었다.(39) (2) RET/PTC 재조합 : RET는원래신경세포표면에존재하는수용체결합티로신인산화효소 (receptor tyrosine kinase) 이다. 현재까지 neurotropic factor, neurturin, persephin, artemin 등 4종의 ligand가존재한다고알려져있다.(40) 림프종환자의 DNA를세포주에삽입 (transfection) 하는실험을통해처음발견되었다. 세포주를암화시킨유전자는재조합이일어난상태로존재하고있음이밝혀졌고, 자연스럽게 RET (rearranged during transfection) 이라는이름을얻었다.(41) 원래갑상선여포세포 (follicular cell) 에서는발현하지않고부여포세포를포함한신경내분비 (neuroendocrine) 세포에서만발현한다.(23) RET 유전자의재조합은주로갑상선유두암 (papillary thyroid cancer, PTC) 의발생에관여하기때문에재조합이일어난 RET를 RET/PTC라고부른 Table 1. Genetic rearrangements found in papillary thyroid carcinomas Gene name Oncogene name Fusion gene name Original function of the fusion gene Fusion gene location RET RET/PTC1 H4 Unknown 10q21 RET/PTC2 PRKAR1A camp-dependent protein kinase regulatory subunit RIalpha 17q23-24 RET/PTC3 ELE1 Androgen receptor coactivator 10q11.2 RET/PTC4 ELE1 Androgen receptor coactivator 10q11.2 RET/PTC5 RFG5 Golgi autoantigen 14q RET/PTC6 HTIF1 Thought to associate with chromatin and 7q32-34 heterochromatin-associated factors RET/PTC7 RFG7 Thought to be a transcriptional corepressor 1p13 RET/PTC8 KTN1 Microtubule-associated protein 14q22.1 RET/PTC8? RFG8 Unknown 18q21-22 NTRK1 TRK TPM3 Tropomyosin family of actin-binding proteins 1q21.2 TRK/T1 TPR Forms intranuclear filaments attached to the inner surface 1q25 of nuclear pore complexes TRK/T2 TPR Forms intranuclear filaments attached to the inner surface 1q25 of nuclear pore complexes TRK/T3 TFG TRK-fused gene 3q12.2 TRK/T4 TPR Forms intranuclear filaments attached to the inner surface 1q25 of nuclear pore complexes BRAF AKAP9-BRAF AKAP9 PKA binding anchor protein 7q21

4 4 대한내분비외과학회지 : 제 10 권제 1 호 2010 다.(42) RET/PTC는 RET 유전자의 3 부분이다른유전자의 5 부분과결합하는형태로일어나며결합하는유전자에따라현재 11종류의 RET/PTC가알려져있다 (Table 1). 방사선노출로인해발생하는갑상선유두암의 80% 는 RET/PTC 1 형 (RET/PTC1) 또는 3형 (RET/PTC3) 이며일반적으로 RET/ PTC라고하면이들을지칭한다.(43,44) 정상적인 RET 수용체는자극이왔을때두개의수용체가모여이형체 (dimer) 를이루고이와동시에서로의티로신인산화효소 (tyrosine kinase) 부위를자가인산화 (autophosphorylation) 시킨후하위의단백질로신호를전달하여 MAPK 및 PI3K 신호전달체계를자극한다.(36,45,46) 재조합이일어나서 RET/PTC 형태가되면항상이형체상태로세포질에위치하며, 따라서티로신인산화효소부위가항상인산화되어하위신호전달체계를활성화하게된다.(47) 방사선에노출된경우발생빈도가높아지는데체르노빌사건으로방사능에노출된아이들에게유두암이발병한경우 80% 가 RET/PTC로인한유두암이었다.(48,49) 하지만유두암외에도여포선종,(50) 갑상선종,(50) 하시모토갑상선염,(51-53) 그리고방사선노출과관련없는유두암 (54) 등에서도발견된다. 방사선노출경력이없는유두암에서 RET/ PTC가발견되는경우는대부분이소아환자이다.(42,55) 갑상선미세유두암 (papillary microcarcinoma) 에서도높은빈도로발견되지만저분화암이나역형성암에서는발견되지않는다.(2) RET/PTC가존재하는유두암의경우림프절전이확률이증가하지만예후는오히려좋은편이다.(56) RET/ PTC는갑상선유두암의 3 77% 정도에서발견된다고알려져있는데검사방법및연구기관이속한지역에따라편차가크다. 또한갑상선암자체가다양한 (heterogeneous) 세포의모임이어서검사부위에따라서편차가나타나는것으로생각되고있다.(57) 물론알려지지않은방사선노출이있었거나방사선노출외의다른유두암유발인자가존재할가능성도배제할수없다. 한국인을대상으로조사한결과갑상선유두암환자의약 10% 에서 RET/PTC1 또는 RET/ PTC3가발견되었다.(58,59) 체외에서배양한갑상선세포에 RET/PTC1 또는 RET/ PTC3 유전자를넣어주면세포를암화시키지만그효과가미미하다. RET/PTC가주입된세포는또한 TSH 신호전달체계에변화를발생하긴하지만 TSH 없이성장하지못하며, 유전자불안정성 (genetic instability) 도유발되지않는다.(2) 하지만갑상선특이적유전자의발현이감소하고 MAPK 신호전달체계가활성화된다고보고되었다.(60) RET/PTC를발현시킨형질전환마우스는성장과정에서갑상선유두암이발생하지만종양의성장속도가느리고전이를하지않는다.(44) 방사선노출로인해발병하는갑상선유두암에서는 NTRK1 재조합, AKAP9-BRAF 재조합등이발견되는경우도있다. (3) RAS 돌연변이 : RAS 유전자는랫트 (rat) 에게육종을 일으키는바이러스에서처음분리되었기에 RAS (rat sarcoma) 라는이름으로불린다.(61,62) H-RAS, K-RAS, N-RAS의세종류가있는데갑상선암에서는세가지모두발견된다.(2) 다양한종류의성장인자수용체에서, 특히수용체결합티로신인산화효소로부터신호를전달받아세포내로연결하는역할을한다. RAS 단백질은비활성화상태일때는 GDP (guanosine diphosphaste) 와결합하고있다가활성화신호를받으면 GTP (guanosine triphosphate) 와결합하면서활성화되어 MAPK 및 PI3K 신호전달체계로신호를전달한다. RAS에돌연변이가생기면 GTP를 GDP로되돌리는 GTPase 부위가제역할을못하게되거나 (61번코돈의점돌연변이 ) GTP와의결합력이강화되어 (12번또는 13번코돈의점돌연변이 ) 항상활성화상태가된다.(23) RAS 돌연변이는다양한종류의암에존재하며전체악성종양의약 30% 정도에서발견된다.(2) 유두암 (7 15%) 및여포암 (11 45%), 저분화암 (24 55%), 역형성암 (52 55%) 으로갈수록 RAS 돌연변이의빈도가증가한다.(63,64) 유두암에서는대부분여포성 (follicular variant) 유두암에서 RAS 돌연변이가확인된다.(23) 미세유두암에서도발견되어갑상선암발생의초기단계에관여하는것으로여겨지고있다.(65,66) 예후가나쁜암에서더높은빈도로발견된다.(63) RAS 돌연변이는 PAX8-PPARγ와같이존재하는경우가없어상호간에상호배제성이있는것으로생각된다.(3) RAS 돌연변이가존재하는갑상선암은유두암의특징적인핵형 (nuclear feature) 이없고, 피막이형성되어있는경우가흔하며, 림프절전이의확률이낮다. 반면원격전이 (distant metastasis) 의확률이높고, 암세포의분화도가낮아갑상선특이적단백질의발현이적다. 또한좋지않은예후와연관되는것으로알려져있다. 특히세포주실험에서염색체불안정성 (chromosomal instability) 를촉진시키는것으로밝혀졌는데, 역형성암에서 RAS 돌연변이가높은빈도로발견되는것은이에기인하는것으로생각된다.(23) 양성인여포선종 (follicular adenoma) 에서비율은약간낮지만 (30%) RAS 돌연변이가발견되기에양성선종 (adenoma) 과악성종양 (carcinoma) 를구분짓는분자마커로사용하기에는한계가있다.(23) 갑상선에서 N-RAS가과발현하도록조작한마우스에서는주로여포암이발생하였으며시간이경과하면서저분화암으로진행하였다.(67) (4) PAX8-PPARγ 재조합 : PAX8 (paired box gene 8) 은갑상선세포의성장에중요한역할을하는전사인자 (transcription factor) 이며갑상선이외의세포에서는발현하지않는다.(23) PPARγ (peroxisome proliferator-activated receptor gamma) 는세포성장및세포사멸을조절하여종양억제단백질 (tumor suppressor) 역할을하는핵내호르몬수용체 (nuclear hormone receptor) 이다.(68) 염색체재조합에의해이들두유전자가결합된형태로발현하는것을 PAX8-

5 이규언외 : 여포세포유래갑상선암의유전자이상 5 PPARγ라고부르며이경우 PPARγ 기능이억제된다. 이는만들어진단백질이정상단백질의기능을방해하는 (dominant negative) 역할을하기때문으로생각된다.(69) PPARγ의기능억제또는발현감소가정상세포를암세포로변화시키는정확한기작은아직밝혀지지않았다.(3) PAX8-PPARγ는여포선종의 4 33%, 여포암의 36 45%, 여포성유두암의 37.5% 에서발견된다.(69-72) 반면여포암의변종인허틀세포암 (Hurthle cell carcinoma) 에서는거의발견되지않는다.(23) PAX8-PPARγ 재조합으로인해발병하는갑상선암은환자의나이가어리고, 종양의크기가작고, 혈관침윤의빈도가높다는특징이있다.(2) 세포주실험과동물실험및사람을대상으로하는임상실험을통해 PPARγ가종양억제단백질의역할을하는것이증명되었다.(73-75) PAX8-PPARγ가존재하는여포암과존재하지않는여포암을비교한결과유전자발현양상에큰차이를보였으며, 이는 PAX8-PPARγ가다양한신호전달체계에관여하기때문인것으로생각된다.(76) 그리고 PAX8-PPARγ가존재하지않는여포암에서도 PPARγ의발현이감소한경우가많아, 이를조절하는다른유전적인변화가있을것으로추측된다.(70) (5) PI3K 신호전달체계상의유전자이상 : 갑상선암특히여포암은 PI3K 신호전달체계가활성화된경우가많다. EGF, IGF-I 등성장인자의신호를받으면세포표면의수용체 ( 특히수용체결합티로신인산화효소 ) 가이들을감지하고 PI3K가세포막내부의 PIP3로신호를전달, AKT를활성화시켜다양한유전자의발현을조절한다.(77) PI3K 신호전달체계는세포성장에중요한역할을하며갑상선암을포함하여흑색종, 대장암, 자궁내막암등다양한종류의종양에서 PI3K 신호전달체계의이상이발견된다.(78-81) PI3K 신호전달체계에이상이생기는것은크게 PTEN의기능이감소된경우, PIK3CA의기능이강화된경우, 그리고 AKT 의기능이강화된경우로나눌수있다.(2,82) PTEN은 PI3K가 PIP3를활성화시키는것을억제하여 PI3K 신호전달체계를조절하는종양억제단백질 (tumor suppressor) 이다. PTEN이제기능을못하는원인은 PTEN 유전자의삭제 (deletion), PTEN 돌연변이, PTEN 유전자메틸화등이있다.(2) PI3K는효소부위 (p110 catalytic subunit) 와조절부위 (p85 regulatory subunit) 으로이루어지며효소부위는 A형또는 B형이있다. PIK3CA는 A형의효소부위를만드는유전자이다.(83) PIK3CA의유전자수증가 (copy number gain) 또는활성화돌연변이가일어나면 PI3K의기능이강화되어 PI3K 신호전달체계가활성화된다.(83) AKT는 PI3K 신호전달체계에서세포사멸을억제하는역할을하는단백질이며종양에서과발현되는경우가많다. 갑상선암에서는확인되지않았지만, AKT 자체에도돌연변이가존재한다고알려져있다.(82,84) PTEN에선천적인돌연변이가있어정상기능을못하게 되는경우 PI3K 신호전달체계가활성화되어 Cowden 증후군이발생한다. 이들에게갑상선여포암의발생확률이높다는사실에서 PI3K 신호전달체계가여포암발생에중요한역할을함을알수있다.(85) 유전적돌연변이외에체세포돌연변이도여포암의발생확률을높인다고보고되었으며, 돌연변이등의이유로 PTEN이제기능을못하고있는경우가비유전성여포암의 20 30% 에달함이알려져있다.(86,87) 여포선종의경우또한 PTEN의불활성화가보고되었다.(88) 역형성암의 50% 이상에서 PTEN이정상적으로작용하지못한다는사실에서갑상선암이진행할수록 PI3K 신호전달체계가중요하게작용함을알수있다.(77,89) 물론 PIK3CA의돌연변이또는과발현이원인이되는여포암도많다.(90,91) PTEN 발현을없앤형질전환마우스에서갑상선종및여포선종만발생하고여포암이발생하지않는다는사실에서 PIK3CA 또한중요한역할을한다고유추할수있다.(92) PI3KCA 돌연변이는 PTEN 유전자이상과비슷한빈도를보이는데여포암의 8 29%, 역형성암의 23% 에서발견된다.(93) 2) 갑상선저분화암및역형성암에서발생하는유전자이상저분화암 (poorly differentiated thyroid cancer) 및역형성암 (anaplastic thyroid carcinoma) 은유두암및여포암이진행하여발생한다고알려져있다. 분화암 ( 유두암및여포암 ) 에서저분화암, 역형성암으로진행하면서분화암의특징이점차적으로사라지고역형성암의특징인세포분열 (mitosis), 세포괴사 (necrosis), 핵의다형성 (nuclear pleomorphism) 이많이발견된다는사실에서이를확인할수있다. 또한역형성암병변에유두암또는여포암의일부가동반된다는사실과유두암또는여포암이재발을거듭할수록역형성암의특징을보이는점도이를지지한다.(3) 역형성암은유두암 (40 50%), 여포암 (60 75%) 보다높은빈도 (85 100%) 의염색체이상을보인다.(9,12-15) 역형성암은 p53, β-catenin 등의 Fig. 2. Thyroid carcinoma progression model.

6 6 대한내분비외과학회지 : 제 10 권제 1 호 2010 유전자이상과관계있음이알려져있다.(3) BRAF, RAS, PIK3CA, PTEN 등의유전자이상은역형성암에서도발견되지만 RET/PTC 재조합, PAX8-PPARγ 재조합은발견되지않는다 (Fig. 2).(16) (1) p53: p53은 DNA의손상을방지하고세포주기를조절하여세포의암화방지역할을하는중요한종양억제단백질 (tumor suppressor) 이다.(94) 세포에이상이감지되면 p53 이작동하여세포성장을정지시킨후손상된 DNA를복구하게되며복구가어려운경우세포사멸 (apoptosis) 를유도한다.(95) P53에돌연변이가일어나면 DNA에결합하지못하여 DNA 손상복구의역할을할수없게된다.(3) MDM2 는 p53가과발현되지않도록조절하는역할을하는데, MDM2가어떠한원인에의해과발현되면세포내 p53의양을감소시켜유사한효과를내기도한다.(96) 또는 MDM2 가과발현되지않도록조절하는 p14 ARF 단백질의발현양이감소하여결과적으로 p53이제기능을하지못하는경우도있다.(97,98) p53 돌연변이는인체종양의 50% 정도에관여한다.(99) 유두암및여포암에서는거의발견되지않고저분화암 (50%) 및역형성암 (80%) 에서높은비율로 p53 돌연변이가발견된다.(100) 이때발견되는돌연변이는대부분 72번코돈의돌연변이이다.(101) MDM2는유두암및여포암에서저분화암, 역형성암으로진행할수록발현이오히려감소하는데이는돌연변이상태의 p53이정상상태일때와는달리 MDM2의발현을촉진시키지못하기때문 (lack of feedback loop) 으로생각된다.(102) 실제 MDM2는종양의종류에따라악성도에비례하기도하고반비례하기도하여종양의분자마커로사용하기가힘들다.(103) 갑상선세포에돌연변이 p53을넣어준실험에서 p53 돌연변이만으로는한천 (soft agar) 에군집 (colony) 를형성하지못함이밝혀졌으며누드마우스주입시에도종양을발생시키지못하였다. 따라서 p53 돌연변이는다른발암유전자가이미존재하는상황에서만세포성장촉진및역분화 (dedifferentiation) 에관련된역할을하리라생각된다.(3) 앞에서언급하였지만 RET/PTC 형질전환마우스에서는전이하지못하는유두암이발생하는데, p53이없는마우스와교잡시키면저분화및역형성암이발생한다. 이를통해 p53의기능상실은갑상선암진행과정후기에역할을하리라생각할수있다.(104) (2) β-catenin: β-catenin은 Wnt 신호전달체계에관여하는단백질이다.(105) 정상상태의세포에서는세포질에위치하며 APC-axin 복합체에의해분해되기때문에소량존재한다.(106) 하지만 APC-axin 복합체에이상이있거나 β- catenin 자체에이상이발생하는경우분해되지않고고농도로존재하게된다. 핵으로이동하여핵내부에고농도로존재하는경우도있다. 유두암및여포암 (0%), 저분화암 (21 25%), 역형성암 (48 66%) 으로갈수록세포핵에존재하는 β-catenin의비율이높아짐이보고되었다.(107,108) 또한 β- catenin 돌연변이는유두암이나여포암에서는발견되지않고저분화암 (32%) 이나역형성암 (61%) 으로갈수록발생확률이높아진다고알려져있다.(107,108) 역형성암에서 Axin 과 APC 유전자의돌연변이는 82% (Axin) 와 9% (APC) 에서발견되었다.(109) 3) 제노믹스와프로테오믹스를이용한갑상선암연구제노믹스 (genomics) 는유전자의, 프로테오믹스 (proteomics) 는단백질의총체적인발현양상을연구하는학문이다. 마이크로어레이 (microarray) 기술의개발로 DNA에서전사되는 mrna의발현양상을확인할수있게되면서신체적이상에동반되는유전자의발현양상을파악하는것이가능해졌는데, 특히악성종양의진단및예후예측에이를이용하고자하는움직임이활발하다. 하지만생체내에서유전자의유전정보는단백질로번역된후에야고유의특성을나타내므로 mrna의발현양상을기반으로한해석은실제체내에서일어나는현상과차이를보인다는단점이있다. 프로테오믹스는이를보완하여단백질자체의발현양상을확인하는연구방식이다. 개개의유전자는 alternative splicing, 번역후변형 (post-translational modification) 등을통해더욱다양한종류의단백질을만들어내기때문에프로테오믹스는제노믹스에비해총체적관점의연구라할수있다. 프로테오믹스에관련된기술의발전과함께학자들의관심도제노믹스에서프로테오믹스로옮겨가고있는추세이다. 마이크로어레이 (microarray) 를이용한연구에서는여러유전자의조합 (classifier) 을이용하여암종을구분하려는시도가많이이루어진다. 갑상선암의경우를살펴보면, Mazzanti 등은양성종양 (hyperplastic nodule) 과유두암에서 6종의유전자 (C21orf4, Hs.24183, Hs , KIT, LSM7, SYNGR2) 의발현양상차이를발견하였고,(110) Weber 등은 CCND2, PCSK2, PLAB를 classifier로이용하여여포선종과여포암을구분하였다.(111) Foukakis 등은 TERT, TFF3, PPARG, CITED1, EGR2를이용하여예후가나쁜여포암을구분하였다.(112) 다른종양, 특히유방암및폐암에서는수십개의유전자조합을이용하여대규모환자군을대상으로한연구가진행된바있으며기존의예후예측인자와명확한상관관계를보였지만,(113,114) 갑상선암에서는아직그와같은대규모연구가진행된바없다. 포로테오믹스 (proteomics) 연구도갑상선암을비롯한많은악성종양의연구에사용되고있다. 특히유방암등일부암에서는단백질의발현양상을실제진단, 예후예측, 항암제반응성등을예측하는데사용하고자하는이행성연구 (translational reaserch) 를활발하게진행하고있다. 갑상선암에서의연구는이에비해단순비교단계에머무르고있는데, Brown 등은유두암에서양성종양에비해 Cathepsin B,

7 이규언외 : 여포세포유래갑상선암의유전자이상 7 CK19, Gal-3, S100A4, Prx2, HSP70 등의단백질발현이증가함을보고하였고,(115) Netea-Maier 등은 PDIA3, HSP90, Calreticulin, TPO 등의단백질이여포암에서여포선종에비해감소함을보고하였다.(116) 기존의연구가주로종양조직에초점을맞춘것이었다면, 인간의혈액, 침, 소변등의체액 (body fluid) 를대상으로진행되는연구가앞으로는더욱많아질것으로여겨진다. 이를통해궁극적으로는프로테오믹스를이용한진단법의개발과같은실제임상에적용할수있는기술의발전이기대된다. 결 갑상선암의발생및진행에는다양한종류의유전자이상이관여한다. 갑상선암은분화암 ( 유두암, 여포암 ) 과저분화암, 그리고역형성암으로진행하면서더욱악성도가높은유전자이상에노출되는것으로여겨지며, 따라서종양의진행과정을연구하기에좋은모델이된다. 또한유전자의재조합으로인해갑상선암이발생하는경우도많아원인에대한추가연구도필요하다. 유전자또는단백질의발현양상을갑상선암의진단및예후예측에이용하고자하는연구또한활발하다. 갑상선암에서발생하는유전자의이상에대해연구하는것은궁극적으로갑상선암의진단및치료를위한기반이된다는사실에그의의가있다. 론 REFERENCES 1) Burman KD, Ringel MD, Wartofsky L. Unusual types of thyroid neoplasms. Endocrinol Metab Clin North Am 1996;25: ) Riesco-Eizaguirre G, Santisteban P. New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy. Endocr Relat Cancer 2007;14: ) Wreesmann V, Singh B. Clinical impact of molecular analysis on thyroid cancer management. Surgical Oncology Clinics of North America 2008;17: ) El-Shabrawi Y, Mangge H, Hermann J. Anti-tumour necrosis factor alpha treatment in chronic recurrent inflammation of the anterior segment of the eye in patients resistant to standard immunomodulatory treatment. Ann Rheum Dis 2003;62: ) Roque L, Rodrigues R, Pinto A, Moura-Nunes V, Soares J. Chromosome imbalances in thyroid follicular neoplasms: a comparison between follicular adenomas and carcinomas. Genes Chromosomes Cancer 2003;36: ) Kitamura Y, Shimizu K, Ito K, Tanaka S, Emi M. Allelotyping of follicular thyroid carcinoma: frequent allelic losses in chromosome arms 7q, 11p, and 22q. J Clin Endocrinol Metab 2001;86: ) Castro P, Eknaes M, Teixeira MR, Danielsen HE, Soares P, Lothe RA, et al. Adenomas and follicular carcinomas of the thyroid display two major patterns of chromosomal changes. J Pathol 2005;206: ) Wreesmann VB, Ghossein RA, Hezel M, Banerjee D, Shaha AR, Tuttle RM, et al. Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity. Genes Chromosomes Cancer 2004;40: ) Roque L, Nunes VM, Ribeiro C, Martins C, Soares J. Karyotypic characterization of papillary thyroid carcinomas. Cancer 2001;92: ) Singh B, Lim D, Cigudosa JC, Ghossein R, Shaha AR, Poluri A, et al. Screening for genetic aberrations in papillary thyroid cancer by using comparative genomic hybridization. Surgery 2000;128:888-93;discussion ) Kjellman P, Lagercrantz S, Hoog A, Wallin G, Larsson C, Zedenius J. Gain of 1q and loss of 9q21.3-q32 are associated with a less favorable prognosis in papillary thyroid carcinoma. Genes Chromosomes Cancer 2001;32: ) Roque L, Soares J, Castedo S. Cytogenetic and fluorescence in situ hybridization studies in a case of anaplastic thyroid carcinoma. Cancer Genet Cytogenet 1998;103: ) Mark J, Ekedahl C, Dahlenfors R, Westermark B. Cytogenetical observations in five human anaplastic thyroid carcinomas. Hereditas 1987;107: ) Jenkins RB, Hay ID, Herath JF, Schultz CG, Spurbeck JL, Grant CS, et al. Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Cancer 1990;66: ) Rodrigues RF, Roque L, Krug T, Leite V. Poorly differentiated and anaplastic thyroid carcinomas: chromosomal and oligo-array profile of five new cell lines. Br J Cancer 2007;96: ) Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer 2009;16: ) Rapp UR, Goldsborough MD, Mark GE, Bonner TI, Groffen J, Reynolds FH Jr, et al. Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci U S A 1983;80: ) Nucera C, Goldfarb M, Hodin R, Parangi S. Role of B-Raf (V600E) in differentiated thyroid cancer and preclinical validation of compounds against B-Raf (V600E). Biochim Biophys Acta 2009;1795: ) Leicht DT, Balan V, Kaplun A, Singh-Gupta V, Kaplun L, Dobson M, et al. Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta 2007;1773: ) Emuss V, Garnett M, Mason C, Marais R. Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res 2005;65: ) Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature

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