Clinical Genomics
정연준
Catholic University Medical College, Seoul, Korea
4 체액설 (blood, phlegm, yellow bile, black bile) Eukrasie vs Dyskrasie Hipocrates 현대의학 GATC 유전자의 변이 및 다형성 으로 질병 설명 맞춤 의학
의료 패러다임의 변화
현재 미래유전자
유전체
돌연변이
유전적 다형성
원인
위험인자
원인 제거
인자 관리
환자
고객
맞춤의학
선천적 소인
(질병감수성,
약물반응 차이 ..)
•예방 (genetic susceptibility marker)
•맞춤치료 (molecular/pharmacogenomics marker)
병인
CML: genetic target의 상징
JAK2
V617F
Polycythemia Vera: genetic target의 재발견
발암유전자 Bcr-Abl의 발견 표적치료제의 개발 치료패러다임의 혁신
원인미상 유전자연구 기법의 발전 JAK2 유전자변이의 발암기전 규명
표적치료
실행중인 맞춤의학 사례
JAK2 inhibitor (Ruxolitinib…) Gleevec Nilotinib
BRAF V600E vemurafenib BRAF/EGFR cetuximab EGFR , EML4-ALK Iressa® (gefitinib), crizotinib HER2 Herceptin® (trastuzumab)
신약개발
Vemurafenib Herceptin Gefitinib Gleevec M-ab Bcr-AblClinical Sequencing
• Whole exome seq • Target seq (Cancer Panel)
Confirm!
(PDX)Informatics
• WES • Target seq • Liquid BiopsyClinical Sequencing for Precision Medicine
• Shift emphasis in medicine from reaction to prevention
• Select optimal therapy and reduce trial-and-error prescribing
• Make drugs safer by avoiding adverse drug reactions
• Increase patient adherence to treatment
• Improve quality of life
• Revive drugs that failed in clinical trials or were withdrawn
from the market
• Help control the overall cost of health care
전장 Exome sequencing
New Genetic Test
단일 유전자 부분 검사 차세대 염기서열 분석
(맞춤유전체분석)
Oncotype DX® 21-Gene
Recurrence Score (RS) Assay
PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68
16 Cancer and 5 Reference Genes From 3 Studies
Category
RS (0 -100)
Low risk RS <18
Int risk RS 18 - 30
High risk RS ≥ 31
Paik et al. N Engl J Med. 2004;351:2817-2826.
RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score
+ 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68
- 0.08 x GSTM1 - 0.07 x BAG1
B-20 Results: Tam vs Tam + Chemo
28% absolute benefit from tam + chemo
Paik et al. J Clin Oncol. 2006.
0 2 4 6 8 10 12 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 D RF S
Low Risk Patients (RS < 18) Tam + Chemo Tam p = 0.61 0 2 4 6 8 10 12 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 D RF S Int Risk (RS 18 - 30) Tam + Chemo Tam p = 0.39 Low RS 0 2 4 6 8 10 12 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 D RF S
High Risk Patients (RS 31) Tam + Chemo
Tam
p < 0.001
Int RS
High RS
High Risk Patients (RS≥31) N Events TAM + Chemo 117 13
TAM 47 18
Low Risk Patients (RS<18) N Events TAM + Chemo 218 8 TAM
135 4
Int Risk Patients (RS 18-30) N Events TAM + Chemo 89 9 TAM 45 4 Pr opor tion wi th ou t D is tan t Rec ur ren ce
병합처방 (항암제+항우울제..)에도 유전형고려
Control cost of health care
Warfarin
genetic testing to target dosing of the blood thinner drug warfarin
could prevent 17,000 strokes in the U.S. and could avoid as many as 43,000 visits to the emergency room
Oncotype Dx®
the savings in terms of adjuvant chemotherapy, supportive care and management of adverse events would be about $1,930 per patient tested
Erbitux® (cetuximab)
limited to those patients with metastatic colorectal cancer whose KRAS gene is not mutated
$604 million could be saved annually
정밀 의학
선천적 소인
(질병감수성,
약물반응 차이 ..)
•예방 (genetic susceptibility marker)
•맞춤치료 (molecular/pharmacogenomics marker)
병인
Gifu-Aomori Study
• Development of personalized prevention
systems
– Collection of clinical and genotype information from
subjects
• Ischemic or hemoragic stroke 1200 • Myocardial infaction 1200
• Hypertension 2900
• Stent implantation 700
• Type 2 diabetes melitus 1500 • Metabolic syndrome 1100 • Obesity 1200
• Healthy control 1000
– Prediction of the risk for diseases
The risk factors of myocardial infarction
• Environmental
– Sex (5.37) – Hypercholesterolemia (3.16) – Diabetes melitus (2.62) – Hypertension (2.20)• Genetic
– FABP2 (1.34) – AKAP10 (1.93) – IPF1 (0.72) – GP1BA (1.36) – MTHFR (1.40) – ACDC (1.25) – F7 (0.70) (odd ratio)Personalized prevention of
myocardial infarction
Hypercholestero lemia yes 3.16 Diabetes melitus yes 2.62 Hypertension yes 2.20 Smoking yes 1.71 FABP2 yes 1.34 AKAP10 yes 1.93 IPF1 no 0.72 GP1BA yes 1.36Risk probability
70%
Risk probability
15%
Improvement of life style Medical treatmentFor Clinical Translation
• 과학적으로 타당한 검사법
– 유전체 연구 및 임상시험
– 평가, 승인제도
• 유전정보의 임상 활용
– 개인정보 보호관련 제도
– 전문가 양성을 위한 교육
– 적절한 의료제도
• 사회문화적 여건
– 대중의 유전체에 대한 올바른 이해
임상적 유효성 평가
유효성 입증 유효성 미입증 건강보험 항목 (약 300여종) 2013년 10월 30일 서울대병원 박성섭 교수 강의자료 진단/검사 소인예측 유효성 입증 과학적 근거 확보노력 관련자료: http://kams.or.kr/webzine/13vol39/sub02.phpGenome Transcriptome
Proteome
Druggable Target
High throughput drug screening
PDX 임상(개인 맞춤치료) 적용
가능성
45
