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1 대한내과학회지 : 제 79 권제 2 호 2010 특집 (Special Review) - 대장암의조기발견및치료에대한전략 대장암의유전학적관련성의최신지견 성균관대학교의과대학삼성서울병원소화기내과 김영호 Understanding of molecular pathogenesis and genetic markers in colorectal cancer Young-Ho Kim, M.D. Department of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Colorectal cancers results from the progressive accumulation of genetic and epigenetic alterations that lead to cellular transformation and tumor progression. Genomic instability, including chromosomal translocations and microsatellite instability, plays a role in acquisition of enough mutations for malignant transformation. In addition, epigenetic silencing is an important mechanism in the evolution of a subgroup of colorectal cancers. These genetic and epigenetic changes causes activation of oncogene pathway (APC, KRAS) and inactivation of tumor-suppressor pathway (p53, TGF-β). Recent advance in colorectal carcinogenensis leads to development of molecular markers for early detection and predictive and prognostic markers. (Korean J Med 79: , 2010) Key Words: Colorectal cancer; Genetic instability; Epigenetic change; Biomarker 서론국내에서도급격히증가하고있는대장암의발생원인은아직정확히알려져있지는않으나유전적 (genetic), 후성적 (epigenetic) 변화가축적되면서세포의형질전환이일어나고형질전환된세포의증식을통해종괴가발생하는것으로 알려져있다 ( 그림 1) 1). 대장암은종양의발생에관여하는유전학적기전이많이알려져있는종양중하나로최근이러한유전학적이상을실제임상에적용하여환자의치료에이용하고있다. 본문에서는대장암의발생에관련되는유전학적기전과실제임상에서의응용에대하여살펴보고자한다. Figure 1. A stepwise model of colorectal carcinogenesis

2 - The Korean Journal of Medicine: Vol. 79, No. 2, 본론 1. 대장암의유전학적발생기전종양이형성되는기전에대해서는두가지견해가있는데하나는자연적인확률로돌연변이가발생하고이들돌연변이로생존에유리한형질이선택된다는것이며, 다른하나는돌연변이율이증가하는유전체불안정에의하여종양이발생한다는것이다. 유전체불안정에는염색체불안정 (chromosomal instability) 과미세위성불안정 (microsatellite instability) 이있다. 염색체불안정은대장암의 80~85% 에서발견되는가장흔한유전체불안정이며, 홀배수체 (aneuploidy) 와같은염색체복제수와구조의변화를일으키고유전자발현을광범위하게변화시켜주위환경변화에대응하며성장을조절함으로써세포가생존해나가기에유리한조건을형성한다 1). 미세위성불안정은 DNA의염기- 염기불일치시교정에관여하는유전자들의불활성화로인해발생한다. 유전체내에는짧은길이의서열이반복되는미세위성이산재해있다. 이들반복적인서열에서는일부서열이결손되거나삽입되기쉬운데이러한경우 MSH2, MSH6, MLH1, PMS2 등과같은불일치유전자들이작동하여복구하게된다. 그러나불일치복구유전자들의장애가있으면결손되거나삽입된서열이유지되면서반복적인염기서열을포함하고있는유전자에돌연변이 (frameshift mutation) 를일으킨다 2). 선천적인불일치복구시스템의불활성화는유전성대장암증후군의하나인 Lynch 증후군 (hereditary non-polyposis colon cancer; HNPCC) 의원인이며산발성대장암 (sporadic colon cancer) 의 15% 에서불일치복구시스템에체세포불활성화 (somatic inactivation) 에의한미세위성불안정이관찰된다. 미세위성변이유발경로에서주로발견되는돌연변이는 TGF βrii, activin type II receptor (ACVR2), BAX, SEC65 (a human homologue of a yeast DnaJ-like endoplasmic reticulum translocon component potein gene), AIM2 (an interferon-inducible gene), MSH3, MSH6, RIZ (the retinoblastoma protein-interacting zinc finger gene), CDX2 (an intestinal homeobox factor) 등인데이러한돌연변이들은선종에서대장암으로진행하는전과정에서나타난다. 따라서미세위성불안정은세포의생물학적활성을조절하는중요한유전자들의돌연변이를유발하고이러한돌연변이를축적하는데유리한환경을제공함으로써대장암을유발하게된다. 미세위성불안정대장암은미세위성안정대장암과는다른임상적병리적특징을가지고있는데근위부 대장에주로발생하고미분화형의비율이높으며산발성인경우고령의환자와여자환자에서호발한다. 일반적으로대장암에서염색체불안정과미세위성불안정은역상관관계를가지고있다. 불일치복구시스템이결손되어있는대장암들은대개두배수체이며불일치복구시스템이보존되어있는대장암은홀배수체이며염색체의변화가심하다. 이러한두가지불안정은종양발생의초기에일어나는것으로보이며종양의진행을촉진한다. 대장암의발생에는후성적변화 (epigenetic change) 도중요한역할을하는것으로알려지고있다. 후성적변화란염기서열이변화하지않은상태에서특별한기전에의해유전자의발현양상이변하고, 이러한유전자발현의변화가자손세포에게전달되는현상이다 3-6). 후성적변화의대표적인현상이유전자의촉진자 (promoter) 부위에존재하는 CpG island 의과메틸화 (hypermethylation) 에의하여해당유전자의발현이억제되는것이다. 대표적으로 Lynch 증후군의원인유전자인 MLH1 의촉진자에과메틸화가발생하면산발성미세위성불안정대장암이발생하게된다. 이외에도다양한종양억제유전자 (CDKN2A/p16, MGMT, p14 ARF, HLTF) 의발현이이러한촉진자과메틸화에의하여억제되는것으로알려지고있다 7-13). 또한대장암발생에촉진자의과메틸화가대장암발생에중요한역할을하는특수한표현형으로서 CpG island methylator phenotype (CIMP) 의실체를지지하는연구결과들이발표되고있다 14,15). DNA 메틸화는 s-adenosylmethionine 에서 cytosine의 5번째탄소위치로메틸기를옮기는화학반응으로대부분 cytosine의메틸화는 5'CG3' (CpG dinucleotide) 에서일어난다. 대부분의 CpG sites는진화과정에서소실되어예측치의약 5~10% 만존재한다. 이는메틸화된 cytosine 은 thymine으로변화되는돌연변이가발생하기쉽기때문이다 16). 그러나유전자들의반정도에서 5' 촉진자부위가 CpG dinucleotide가밀집되어있는 0.5~5 kb의크기인소위 CpG island 내에위치하는데, 이부분은정상적으로는불활성화 X-유전자나 imprinted gene을제외하고는메틸화가되어있지않다. 이러한부위에메틸화가발생되면해당유전자의발현이억제되고이유전자가종양억제유전자인경우발암과정을촉진하게되는것이다. 2. 대장암발생에관련된중요신호전달체계 APC 유전자 (gatekeeper) 는가족성선종성용종증 (familial adenomatous polyposis, FAP) 환자들과염색체 5q21과의연관성으로부터발견되었는데 FAP 환자의경우태어나면서부터

3 - Young-Ho Kim. Understanding of molecular pathogenesis and genetic markers in colorectal cancer - 한쪽대립유전자에돌연변이가있으며출생후나머지하나의대립유전자에결손이나돌연변이가발생하면서종양이발생하게된다. 대장암발생의초기에중요한역할을하는 APC 유전자의돌연변이는산발성대장암의약 80% 에서발견되며 APC 유전자에돌연변이가없는경우에는 β -catenin에돌연변이가있어같은 Wnt 신호전달경로를자극하게된다 17,18). Wnt 신호전달경로가활성화되면세포표면의수용체에서핵내로신호를전달하여종양형성이나성장과관련된유전자의발현양상을변화시키게된다. 암유전자 (oncogene) 인 RAS는 HRAS, KRAS, NRAS의세가지형태로존재하는데 molecular switch 의역할을하는 guanosine triphosphate hydrolase (GTPase) 를만든다. RAS 는세포바깥의성장신호를핵내로전달하는역할을하는데 RAS 가활성화되면 Raf/MAPK, PI3K/Akt, Mekk/JNK 등다양한경로를통하여세포를변형 (transformation) 시키게되고 p53 이나 TGF-β 경로와같은종양억제경로를억제하는역할을한다. RAS 중대장암에서가장흔하게돌연변이를일으키는것은 KRAS인데 19) codon 12, 13, 61에집중적으로발생하며 GAP-mediated GTP hydrolysis에저항성을가지게되어지속적으로활성화된상태를유지하게된다. KRAS의돌연변이는산발성대장암이나 1 cm 이상의선종의 50% 에서발견되지만크기가작은선종에서는거의발견되지않아선종의성장단계에관여하는것으로생각된다 20,21). 염색체 17번단완에위치하는 p53 유전자 (Guardian of the Genome) 는가장먼저알려지고가장많이연구되어온종양억제유전자로서여러가지자극에의해활성화되어 p21 WAF1, bax, Fas, KILLER/DR5, σ 등과같은타겟유전자의발현을변화시킴으로써세포주기억제, 세포자멸사 (apoptosis), 노화, 분화, 혈관생성억제등을일으킨다. 대장암의약 70% 까지 17p locus의이형접합체소실 (loss of heterozygosity) 을관찰할수있는데선종에서는거의관찰할수없어 p53의기능소실은대장암발생의마지막단계에서중요한역할을하는것으로보인다 20,22,23). 염색체 18번장완의결손은대장암의 73% 에서관찰되지만진행성선종 (advanced adenoma) 에서는 15% 에서만관찰된다 20). 염색체 18번장완에서발견된첫번째종양억제유전자는 DCC ( deleted in colon cancer ) 이며 24,25) 이후 TGF-β 경로에관여하는 SMAD4, SMAD2가발견되었다 26,27). TGF-β는세포성장및분화, 발생에중요한역할을한다. TGF-β는결합하는세포의종류에따라반응이다르게나타나는데상피세포에서는대개성장을억제한다. 따라서 TGF-β의성장억제효과에대한민감성소실은암발생과관련이있으며대장암을포함한유방암, 췌장암등에서관찰된다. 대장암세포주의약 75% 는 TGF-β 신호전달경로에의해성장이조절되지않는데대장암에서 TGF-β 신호의억제는여러가지방법으로일어날수있지만가장중요한것은수용체인 TGFβRII의돌연변이이며미세위성불안정대장암의약 90% 에서관찰된다. 이는 TGFβRII의염기서열내에두개의미세위성이있어 1~2개의염기쌍이결손되거나삽입되면기능을하지않는단백질이만들어지기때문이다. TGFβRII 의돌연변이는대장암발생의후기에중요한역할을한다. 또한 TGF-β 신호전달경로에관여하는 SMAD 의돌연변이도관찰되는데 18q21에위치한 SMAD4는대장암의약 25% 에서기능이소실되어있으며역시 18q21에위치하는 SMAD2 의경우 5~10% 에서기능이소실되어있다. 3. 유전학의임상적적용 1) 진단대변잠혈검사 (fecal occult blood test) 는수십년간비침습적인대장암선별검사로사용되었으며여러가지연구에서대장암사망률을줄일수있는것으로알려져있다 28-30). 그러나대장암, 특히대장암의전구병변을선별하는데에는민감도가떨어진다는문제점이있다 31). 대변 DNA 검사는대장암에서발생하는돌연변이나촉진자과메틸화를대변에서검출하는방법이다. 2004년, APC, KRAS, P53 등의돌연변이와 BAT-26, long DNA 등을포함한 21개의표지자를대변에서측정하는방법을이용하여대변잠혈검사에비하여대장암에대한민감도가우수함이보고되었고 (52% vs. 13%) 32), 2008년에는 KRAS, APC 유전자의돌연변이와 vimentin 유전자의촉진자과메틸화등세가지표지자를이용한연구에서진행성선종발견율이 46% 로대변잠혈검사의 10~17% 보다우수함이보고되었다 33). 이러한대변 DNA 검사는조기대장암에대하여 46~77% 의민감도를가지고있는것으로알려져있어대변잠혈검사보다우수하며최근미국에서대장암선별검사가이드라인에서선별검사법으로추가되었다 34). 이외에도혈액이나소변에서대장암과관련된 DNA, RNA, 단백질등을찾아선별검사에이용하려는연구들이진행되고있다. 2) 예후및항암제치료에대한반응예측인자예후인자로서가장먼저사용된것은종양억제유전자인 APC, MLH1, MSH2라고할수있다. 가족성선종성용종증

4 - 대한내과학회지 : 제 79 권제 2 호통권제 600 호 의원인인 APC 유전자의생식세포돌연변이가발견된경우예방적전대장절제술 (total colectomy) 이추천되며 Lynch 증후군의원인인 MLH1 이나 MSH2 유전자의생식세포돌연변이의경우종양의성장속도가빠르기때문에 1~2년에한번씩대장내시경검사를권고하며대장암발생시아전대장절제술 (subtotal colectomy) 이추천된다 34). 일반적으로미세위성불안정을보이는대장암은예후가좋으며염색체불안정을보이는대장암은예후가좋지않은것으로알려져있다 35-37). 또한미세위성불안정대장암은보조항암치료에대한반응이불량한것으로알려져있는데이는암세포에서불일치복구시스템의활성화는 5-FU에대한세포독성반응에필요하기때문으로생각되고있다 35,38-41). 그러나 topoisomerase-i 억제제인 irinotecan을이용한항암제치료에서는미세위성불안정을가지는종양의생존율이증가함이보고되었다 42,43). 한편, CIMP 가대장암의예후나항암치료에대한반응에어떠한영향을미치는가에대해관심이많지만아직일치된견해가없다. 최근여러가지표적치료제의개발과함께이들약제에대한반응을예측할수있는인자들에대한연구들이활발히진행되고있다. 가장대표적인것이 epidermal growth factor receptor (EGFR) 단클론항체와 KRAS 유전자의돌연변이에관한것이다. EGFR 은 KRAS 신호전달체계를통하여세포의성장과전이를촉진하기때문에 KRAS 신호전달체계에이상이있는경우즉, KRAS나 BRAF에돌연변이가있는경우 EGFR을차단하는효과가감소할수있다. 실제로 KRAS 돌연변이와 BRAF 돌연변이는 cetuximab이나 panitumumab 과같은 EGFR 단클론항체의치료효과감소를예측할수있는표지자이다 44-46). 약물유전학에대한연구도활발히진행되고있다. 5-FU 의중요타겟은 thymidylate synthetase (TS) 인데 TS의활성도가증가되어있는유전자다형성을가지고있는환자에게서는 5-FU의효과가감소될수있다 47). 또한 irinotecan은 UGT1A1 에의해해독되는데 UGT1A1의발현이감소되는유전자다형성을가지고있는경우중성구감소증과같은부작용이증가할수있다 48). 결론대장암의유전학에대한연구는대장암뿐아니라다른암의발생기전에대한이해의폭을넓혀주었는데특히발암기전에있어유전체불안정과후성적변화가중요한역할을 하고있음을규명하였으며암발생에관여되는여러가지신호전달체계를밝혀내게되었다. 나아가서대장암에서발견되는유전적, 후성적변화를이용한새로운조기진단방법이개발되고있으며새로운약제개발과함께대장암의예후와치료반응에대한예측인자로서활용되면서개인맞춤형치료의발전에기여하고있다. 중심단어 : 대장암 ; 유전적불안정성 ; 후성적변화 ; 표지자 REFERENCES 1) Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer 3: , ) Umar A, Risinger JI, Hawk ET, Barrett JC. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer 4: , ) Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349: , ) Verma M, Srivastava S. Epigenetics in cancer: implications for early detection and prevention. Lancet Oncol 3: , ) Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer 4: , ) Momparler RL. Cancer epigenetics. Oncogene 22: , ) Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R. Methylation of the hmlh1 promoter correlates with lack of expression of hmlh1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57: , ) Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB. Incidence and functional consequences of hmlh1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 95: , ) Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD. Biallelic inactivation of hmlh1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A 95: , ) Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16: , ) Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D, Baylin SB. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: ,

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2016 학년도약학대학면접문제해설 문제 2 아래의질문에 3-4분이내로답하시오. 표피성장인자수용체 (epidermal growth factor receptor, EGFR) 는수용체티로신인산화효소군 (receptor tyrosine kinases, RTKs) 의일종으로서세

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