Giáo trình rối loạn thụ thể trong các bệnh ung thư

Tài liệu này dành cho sinh viên, giảng viên viên khối ngành y dược tham khảo và học tập để có những bài học bổ ích hơn, bổ trợ cho việc tìm kiếm tài liệu, giáo án, giáo trình, bài giảng các môn học khối ngành y dược

0Ð+Î1+ĈѪ1*,Ҧ19ӄ758<ӄ1

7Ë1+,ӊ81Ӝ,%¬2

7+Ө7+ӆ%ӄ0Һ79¬7+Ө7+ӆ1Ӝ,%¬2

&È&.,ӆ87ѬѪ1*7È&*,Ӳ$/,*$1'9¬

7+Ө7+ӆ

7ӂ%¬27Ӗ17Ҥ,ĈѬӦ&1+Ӡ7Ë1+,ӊ8

1*2Ҥ,%¬2

&È&1+Ï07+Ө7+ӆ%ӄ0Һ7

&È&1+Ï07+Ө7+ӆ7<526,1(.,1$6(

10

‡ $FXWH0\HORLG/HXNHPLD$0/ /jWKӇEӋQKXQJWKѭPiXWKѭӡQJJһSQKҩWӣQJѭӡLOӟQ

‡ 5ӕLORҥQ167UҩWSKәELӃQFyêQJKƭDWLrQOѭӧQJ

‡ 30 ± FyÿӝWELӃQJHQFLT3

81*7+Ѭ0È8'Ñ1*7Ӫ<&Ҩ37Ë1+

7521*81*7+Ѭ0È8

ERK MAPK

p p

p p

JAK2

Membrane

Activated FLT3

Cytoplasm

5-10% 15-35% rare

INTERNAL TANDEM DUPLICATION (ITD)

(Breitenbuecher F, Blood 2008;113:4074-7)

(D: Aspartic acid, G:Glycine, Y: Tyrosine)

ETV6/FLT3 *Æ<&+8<ӆ1'Ҥ1*7ӂ%¬2

‡ Epidermal Growth Factor Receptor

‡ 167VӕNEH[RQ

‡ 5HFHSWRU[X\rQPjQJWăQJVLQKYjELӋWKyDWӃEjRGLÿӝQJSKiWWULӇQP{

&Ѫ&+ӂ+2Ҥ7+Ï$(*)5

(Ciardiello F, N Engl J Med 2008;358:1160-74)

&È&/2Ҥ,7+Ө7+ӆ+(5

(Ciardiello F, N Engl J Med 2008;358:1160-74)

Ӭ&&+ӂ+2Ҥ77Ë1+(*)5%Ҵ1*7+8Ӕ&

Ӭ&&+ӂ+2Ҥ77Ë1+(*)5%Ҵ1*7+8Ӕ&

(Herbst RS, N Engl J Med 2008;359:1367-80)

(Lynch TJ, N Engl J Med 2004;350:2129-39)

ĈӜ7%,ӂ1(*)57521*81*7+Ѭ3+Ә,

(Lynch TJ, N Engl J Med 2004;350:2129-39)

(Fukui T, Gen Thorac Cardiovasc Surg 2008; 56:97 ±103)

(Kumar A, J Clin Oncol 2008;26:1742-1751)

9ӎ75ËĈӜ7%,ӂ1(*)57521*81*7+Ѭ3+Ә,

(Science 2004;304:1497-1500)

*(),7,1,%9¬(5/27,1,%1*Ă1&+Һ17Ë1+,ӊ8

7Ӯ(*)5ĈӜ7%,ӂ1

(Fukui T, Gen Thorac Cardiovasc Surg 2008; 56:97 ±103)

ĈÈ3Ӭ1*9Ӟ,7+8Ӕ&Ӭ&&+ӂ(*)5

3+Ө7+8Ӝ&.,ӆ8ĈӜ7%,ӂ1

.KX\ӃFKÿҥLJHQMET ÿӓ WUrQEӋQK QKkQXQJWKѭSKәLFyELӇXKLӋQEGFR

[DQK QKѭQJNKiQJJHILWLQLE

ĈiSӭQJYӟLJHILWLQLESKө

WKXӝFNLӇXÿӝWELӃQEGFR

(*)570ĈӜ7%,ӂ1.+È1*7+8Ӕ&

(Engelman JA, Clin Cancer Res 2008;14(10):2895-2899)

.KiQJWKXӕFGRÿӝWELӃQ

EGFR T790M

.KiQJWKXӕFGR FѫFKӃNKiF

Exon 18 Exon 19 Exon 20 Exon 21

*LҧLWUuQKWӵFKXӛL'1$

.+Ҧ26È7ĈӜ7%,ӂ1EGFR

‡ ĈӝWELӃQEGFR WURQJXQJWKѭÿҥLWUӵFWUjQJUҩWKLӃP

‡ 70% - FyELӇXKLӋQ(*)5ĈtFKÿLӅXWUӏFӫDNKiQJWKӇ ÿѫQGzQJ

‡ &HWX[LPDEFyKLӋXTXҧKѫQWUrQEӋQKQKkQFyELӇXKLӋQ PҥQK(*)5GҥQJKRҥWÿӝQJS(*)5 KRһFFyNKX\ӃFKÿҥL

gen EGFR TXDNKҧRViWEҵQJ),6+

.+Ҧ26È7%,ӆ8+,ӊ1(*)5%Ҵ1*),6+

47

PR: partial response, SD: stable disease, PD: progressive disease

/,Ç1+ӊ*LӲ$(*)5.5$69¬%5$)

(Uramoto H, British Journal of Cancer 2007;96,857 ʹ 863)

'ӴĈ2È1ĈÈ3Ӭ1*9Ӟ,7+8Ӕ&Ӭ&&+ӂ(*)5

;iPQKҥ\ÿHQNKiQJ

McCracken et al., CA Cancer J Clin 2007

HER-2 Protein

HER-2 Genes

FISH : DNA

IHC : Protein

Low amplification

E,'/,ZϮҴNG IHC VÀ FISH

Chromosome 17

Centromere Chromosome 17HER2/ neu

PathVysion HER2 DNA probe

Signal Enumeration

HER-2 orange signal : 2

CEP 17 green signals : 2

Ratio = 1.0

HER-2 orange signal : 10

CEP 17 green signals : 4

Ratio = 2.5

>

=

HER2 signal # X 20 nuclei

CEP 17 signal # X 20 nuclei

2.0 (positive)

0ӝWWURQJQKӳQJGzQJWKiFWtQKLӋXQӝLEjROLrQTXDQÿӃQXQJWKѭYj receptor tyrosine kinase (HER- QHX Oj37(13,.$.7

%uQKWKѭӡQJ37(1FyFKӭFQăQJӭFFKӃQӝLWҥLWURQJFRQÿѭӡQJQj\ ĈӝWELӃQFӫD3,.&$JһSWURQJ-PҩWFKӭFQăQJ37(1JһS

WURQJWUѭӡQJKӧSXQJWKѭY~

Nagata et al., Cancer Cell 2004

Fujita et al., Brit J Cancer 2006

N = 37

0ҩWELӇXKLӋQ37(1Oj\ӃX WӕWLrQÿRiQÿiSӭQJNpP

YӟLWUDVWX]XPDE

3KҫQOӟQÿӝWELӃQFӫD3,.&$[ҧ\UDӣH[RQYj

ĈӝWELӃQ3,.&$OLrQTXDQYӟLWLrQOѭӧQJ[ҩXNKLÿLӅXWUӏEҵQJWUDVWX]XPDE (Berns et al, Cancer Cell 2007)

Pandolfi et al, N Engl J Med 2004

(*&*FyӭFFKӃWUӵFWLӃS+(5-NK{QJ"

‡ Gastrointestinal Stromal Tumor (GIST)

67

(Kitamura Y, Cancer Sci 2003; 94: 315 ±320)

Exon 9 Exon 11 Exon 13

Exon 17

3+Æ1%ӔĈӜ7%,ӂ1KIT TRONG GIST

ĈӝWELӃQӣH[RQ

KIT-WT

KIT-mt

Science 2003;299:708-710

3+Æ1%ӔĈӜ7%,ӂ1KIT 9¬3'*)5$

TRONG GIST

(Lasota J, Histopathology 2008)

73

,PDWLQLEWXҫQ

(Blanke CD, J Clin Oncol 2008;26:620-625)

+,ӊ848ҦĈ,ӄ875ӎ*,67%Ҵ1*,0$7,1,%

Lys Val Val

GAG GAG ATA AAT GGA AAC AAT TAT GTT TAC ATA GAC CCA ACA CAA CTT

561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu

CCT TAT GAT

AAG GTT GTT CCT TAT GAT CAC AAA TGG GAG TTT CCC AGA AAC AGG CTG AGT TTT G

Lys Val Val Pro Typ Asp His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe

Lys Val Val

GAG GAG ATA AAT GGA AAC AAT TAT GTT TAC ATA GAC CCA ACA CAA CTT

561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu

CCT TAT GAT

AAG GTT GTT CCT TAT GAT CAC AAA TGG GAG TTT CCC AGA AAC AGG CTG AGT TTT G

Lys Val Val Pro Typ Asp His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe

G T C C T G A G T T A C C

643 644 645 646 Val Leu Ser Tyr

AA G Lys

G T C C T G A G T T A C C

643 644 645 646 Val Leu Ser Tyr

AA G Lys

0Ð+Î1+;8Ҩ7+,ӊ187ӂ%¬20Ҫ0Ӣ%8Ӗ1*75Ӭ1*9¬7,1++2¬1

Exon Exon 11 Exon 13

Exon 17

3+Ỉ1%ӔĈӜ7%,ӂ1KIT TRONG GIST