Kanker-genen: the good, the bad and the ugly
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Transcript of Kanker-genen: the good, the bad and the ugly
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Cancer genesthe good, the bad and the ugly
Peter VandenbergheCentrum Menselijke Erfelijkheid
Hematologie, IG, UZ Leuven
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Cancer genes the good, the bad and the ugly
• Kanker, eindstadium van een meerstappenproces
• Virale oncogenese
• “Gatekeepers”– Oncogenen
– Tumorsuppressorgenen
– Epigenetica en kanker
– Loss-of-heterozygosity en kanker
• “Caretakers” : DNA-herstelmechanismen
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Kanker, eindstadium van een meerstappenproces
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Adenomateuze poliposis coli (APC)de opeenvolgende stadia
Normale coloncrypten Aberrante cryptefocus Villeus adenoom
Invasief carcinoma levermetastasen
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Virussen en kankerRous sarcoma virus (RSV)
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Retrovirale oncogenen, gekidnapte cellulaire genen
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Virale oncogenese door insertionelemutagenese
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Functies van oncogenen
Anti-apoptose
v-sis /PDGFβ
v-erbB /EGFR
Ser/thrPK
Non-receptor
PTK
v-sarc/c-sarcv-abl/c-abl
GEF
GTP
asesv-ras/HRAS-KRAS-NRAS
v-jun/c-junv-myc/c-mycv-fos/c-fos
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Virale oncogenen en hun cellulaire tegenhangers
Virale ziekte v-onc c-onc Locatie functie
Simian Sarcoma v-sis PDGFB 22q13.1 Subunit van PDGFB
Chicken erythroleukemia v-erb B EGFR 7p13-p12 Receptor van EGF
Feline sarcoma v-fms CSF1R 5q33 M-CSF receptor
Harvey rat sarcoma v-ras HRAS1 11p15 Ras-GTPase
Abelson mouse leukemia v-abl ABL 9q34.1 PTK
Avian Sarcoma v-jun JUN 1p32-p31 AP1 transcriptiefactor
Avian myelomatosis v-myc MYC 8q24.1 Transcriptiefactor
Mouse osteosarcoma v-fos FOS 14q24.3-q31 DNA-bindende
transcriptiefactor
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Oncogenen en kanker
• Amplificatie
• Chromosomale translocaties– Fusiegenen, fusietranscripten, fusie-eiwitten– “promotor-swapping”
• Puntmutaties
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NMYC (2p24) neuroblastoma
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46,XY,t(9;22)(q34;q11)
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Flt3 and acute myeloid leukemia
TK domain
TK domain
JM domain
Ig domain
FLT3/ITD
D835?
D835?
intracellular signalingcell proliferation
WT
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Flt3 and acute myeloid leukemia
TK domain
TK domain
JM domain
Ig domain
FLT3/ITD
D835?
D835?
intracellular signalingcell proliferation
WT
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Gain-of-function mutaties van cellulaire oncogenen leiden tot groeifactor-onafhankelijke groei en
cellulaire transformatie
controle
+ groeifactor
Transfectie met oncogen
Transfectie met oncogen+ inhibitor
cellen
dagen
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Burkitt’s lymphoma
Figure 4.13a The Biology of Cancer (© Garland Science 2007)
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G1 phase6-12 h
2n DNAS phase
6-8 h2-4n DNA
G2 phase3-4 h
4n DNA
M1 h
cyclinA +CDK2
cyclinA1/A2 +CDK1 (CDC2)
yclinA1/A2 +CDK1(CDC2)
cyclinB1/B2 +CDK1(CDC2)
cyclinE1/E2 +CDK2
cyclinD1/D2/D3 +
CDK 4/6
R
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• Familiaal retinoblastoma– 40 %– AD– Frequent bilateraal– Zeer jong – Ook osteosarcoma
• Sporadisch retinoblastoma– 60 % (zz)– Unilateraal– Iets oudere leeftijd
Knudson : two-hit hypothese
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Somatische celhybriden en tumorsuppressorgenen
tumorale cel+tumorcel Niet-tumorale cel
46, XX 92, XXXX46, XX
Niet-tumorale cel
92, XXXX
Niet-tumorale cel
90, XXXX, -13, -13
+tumorcel Niet-tumorale cel
46, XX 46, XX
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the 2nd hit bij familiaal retinoblastoma“loss of heterozygosity”
+c
d-a
b
Mitotische
nondisjunctie
-a
b
puntmutatie
-a
b-c
ddeletie
-a
b+c
d
Mitotische
recombinatie
-a
b
c
b-
Mitotische
nondisjunctie+ reduplicatie
-a
b-a
b
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the 2 hits bij sporadische tumoren“loss of heterozygosity”, caveats
+c
dab+
Mitotische
nondisjunctie
-a
b
Mitotische
nondisjunctie+ reduplicatie
-a
b-a
b
puntmutatie
-a
b-c
ddeletie
-a
b+c
d
Mitotische
recombinatie
-a
b
c
b-
methylatie
-a
b-c
d
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G1 phase6-12 h
2n DNAS phase
6-8 h2-4n DNA
G2 phase3-4 h
4n DNA
M1 h
R
cyclinD1/D2/D3 +
CDK 4/6
cyclinE1/E2 +CDK2
cyclinA +CDK2
cyclinA/B +CDK1
cyclinA +CDK1
E2F
E2FRb
Rb
E2F
Kip/cip
ink4
Tumorsuppressorgenen
Rb E2F
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Kanker, een ziekte van de celcyclus
Nature reviews Cancer 1,222-231, 2001
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Adenomateuze poliposis coli (APC)de opeenvolgende stadia
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Hanahan & Weinberg, Cell, 2000, 100: 57-70
Self-sufficiencyin growthsignals
Insensitivity to antigrowth signals
Evasion of apoptosis
Limitlessreplicativepotential
Sustainedangiogenesis
Tissue invasion
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procarcinogenen
carcinogenen
initiator
initiator
initiator
promotor
promotor
Endogeen metabolismeInflammatie
Infectie
Individuele susceptibiliteit
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Genomische instabiliteit
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Cellulair antwoord op DNA-schade
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Genomische instabiliteit
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Cancer genes, the good, the bad, and the ugly
groei
differentiatie
geprogrammeerde celdood
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Cancer genes, the good, the bad, and the ugly
oncogenen
tumorsuppressor-genen
XX
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Cancer genes, the good, the bad, and the ugly