Molecular mechanisms involved into cancer development ...
Transcript of Molecular mechanisms involved into cancer development ...
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Molecular mechanisms involved into
cancer development
Genetic alterations
• Oncogenes
• Tumor suppressor genes
• DNS repair genes
• Telomer and telomerase
Epigenetic alterations
• DNA-methylation
• Micro-RNS expression
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Molecular mechanisms involved into
cancer development
Genetic alterations
• Oncogenes
• Tumor suppressor genes
• DNS repair genes
• Telomer and telomerase
Epigenetic alterations
• DNA-methylation
• Micro-RNS expression
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Mechanisms of protooncogene – oncogene
transformation
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Mechanisms of protooncogene – oncogene
transformation
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EGFR protooncogene – oncogene transformation
(point mutation)
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Mechanisms of protooncogene – oncogene
transformation
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BCL2 protooncogene – oncogene transformation
(translocation – promoter exchange)
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Mechanisms of protooncogene – oncogene
transformation
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BCR (22q11)
1 23 4 5 6 7 8 9 10 11-15 16 17 18 19 20 21 22 23
m-bcr M-bcr -bcr
1b 1a 2 3 4 5 6 7 8 9 1 0 11
töréspontok
régiója
ABL (9q34)
2 31 ALL
CML11 12
13
2 3
Protooncogene – oncogene transformation
(translocation – gene fusion)
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Mechanisms of protooncogene – oncogene
transformation
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HER2
C-MYC
Protooncogene – oncogene transformation
(gene amplification)
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Protooncogene activations involved in human
cancer development
ONCOPROTEIN FUNCTION PROTO-
ONCOGENE
TYPE OF ACTIVATION NEOPLASM
Growth factor SIS
FGF-3
HST
Increased expression
Amplification
Increased expression
Astrocytoma, osteosarcoma
Melanoma, breast-, bladder cancer
Stomach cancer, Kaposi-sarcoma
Growth factor receptor EGFR
FLT3
RET
KIT
MET
Increased expression
Amplification
Point mutation
Point mutation
Point mutation
Lung planocellular carcinoma, glioma
Breast-, ovarium cancer
MEN 2A, 2B, medullary carcinoma
GIST
Papillary renal cell carcinoma
GTP-bindingproteins KRAS
HRAS
NRAS
Point mutation
Point mutation
Point mutation
Lung-, colon-, pancreas cancer
Kidney-, bladder cancer
Melanoma,AML
Non-receptor thirosine kinase ABL
JAK2
Translocation
Point mutation
CML, ALL
PV, ET, MF
Nuclear transcription factor C-MYC
N-MYC
L-MYC
C-JUN
Translocation
Amplification
Amplification
Increased expression
Burkitt lymphoma
Neuroblastoma, SCLC
SCLC
Lung-, colon cancer
Ciklin and ciklin dependent kinase Ciklin D
Ciklin E
CDK4
Translocation
Amplification
Increased expression
Point mutation
Mantle cell lymphoma
Breast-, oesophagus cancer
Breast cancer
Melanoma, glioblastoma
Antiapoptotic protein BCL2 Translocation Follicular lymphoma
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Molecular mechanisms involved into
cancer development
Genetic alterations
• Oncogenes
• Tumor suppressor genes
• DNS repair genes
• Telomer and telomerase
Epigenetic alterations
• DNA-methylation
• Micro-RNS expression
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Mechanisms of tumor suppressor gén inactivations
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Mechanisms of tumor suppressor gén inactivations
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Mechanisms of tumor suppressor gén inactivations
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Mechanisms of tumor suppressor gén inactivations
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Mechanisms of tumor suppressor gén inactivations
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Tumorsuppressor gene inactivation in
hereditary and sporadic cancers
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GENE FUNCTION HEREDITARY NEOPLASMS SPORADIC NEOPLASMS
RB Cell cycle regulation Retinoblastoma, osteosarcoma Retinoblastoma, osteosarcoma,
emlő-, colon-, tüdőcarcinoma
p53 Cell cycle block,
apoptosis, cell aging
Li-Fraumeni-syndroma Most human cancer
APC -katenin block Familiar adenomatosus polyposis,
melanoma
Colon-, stomach-, pancreas cancer
WT1 Nuclear transcription Wilms-tumor Wilms-tumor
p16/p16 Ciklin dependent kinase
inhibitor
Melanoma Breast-, eosophagus,- prostata-, panceras
cancer
BRCA1 DNA-repair Breast-, ovarium cancer Breast-, ovarium cancer
BRCA2 DNA-repair Breast cancer Stomach cancer
VHL Elongin inhibitor vonHippel-Lindau-syndrome Renal cell carcinoma, haemangioma
NF1 RAS, p21 inhibitor Neurofibromatosis 1 Neuroblastoma, melanoma
NF2 Citosleketonstability Neurofibromatosis 2 Schwannoma, meningeoma
PTEN Tyrosine kinase inhibitor Cowden-syndrome Emdometrium-, prostate cancer
Tumorsuppressor genes involved in human
cancer development
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The role of inactivation of RB tumorsuppressor gene in
cancer development
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GENE FUNCTION HEREDITARY NEOPLASMS SPORADIC NEOPLASMS
RB Cell cycle regulation Retinoblastoma, osteosarcoma Retinoblastoma, osteosarcoma,
breast-, colon-, cancer
p53 Cell cycle block,
apoptosis, cell aging
Li-Fraumeni-syndroma Most human cancer
APC -katenin block Familiar adenomatosus polyposis,
melanoma
Colon-, stomach-, pancreas cancer
WT1 Nuclear transcription Wilms-tumor Wilms-tumor
p16/p16 Ciklin dependent kinase
inhibitor
Melanoma Breast-, eosophagus,- prostata-, panceras
cancer
BRCA1 DNA-repair Breast-, ovarium cancer Breast-, ovarium cancer
BRCA2 DNA-repair Breast cancer Stomach cancer
VHL Elongin inhibitor vonHippel-Lindau-syndrome Renal cell cancer, haemangioma
NF1 RAS, p21 inhibitor Neurofibromatosis 1 Neuroblastoma, melanoma
NF2 Cytosleketon stability Neurofibromatosis 2 Schwannoma, meningeoma
PTEN Tyrosine kinase inhibitor Cowden-syndrome Emdometrium-, prostata cancer
Tumorsuppressor genes involved in human
cancer development
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The role of inactivation of p53 tumorsuppressor
gene in cancer development
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GENE FUNCTION HEREDITARY NEOPLASMS SPORADIC NEOPLASMS
RB Cell cycle regulation Retinoblastoma, osteosarcoma Retinoblastoma, osteosarcoma,
emlő-, colon-, tüdőcarcinoma
p53 Cell cycle block,
apoptosis, cell aging
Li-Fraumeni-syndroma Most human cancer
APC -katenin block Familiar adenomatosus polyposis,
melanoma
Colon-, stomach-, pancreas carcinoma
WT1 Nuclear transcription Wilms-tumor Wilms-tumor
p16/p16 Ciklin dependent kinase
inhibitor
Melanoma Breast-, eosophagus,- prostata-, panceras
carcinoma
BRCA1 DNA-repair Breast-, ovarium carcinoma Breast-, ovarium carcinoma
BRCA2 DNA-repair Breast carcinoma Stomach carcinoma
VHL Elongin inhibitor vonHippel-Lindau-szindróma Renal cell carcinoma, haemangioma
NF1 RAS, p21 inhibitor Neurofibromatosis 1 Neuroblastoma, melanoma
NF2 Citosleketonstability Neurofibromatosis 2 Schwannoma, meningeoma
PTEN Tyrosine kinase inhibitor Cowden-syndrome Emdometrium-, prostata carcinoma
Tumorsuppressor genes involved in human
cancer development
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The role of APC in the development of
adenomatosus polyposis coli
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Molecular mechanisms involved into
cancer development
Genetic alterations
• Oncogenes
• Tumor suppressor genes
• DNS repair genes
• Telomer and telomerase
Epigenetic alterations
• DNA-methylation
• Micro-RNS expression
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The role of DNA mismatch repair in
cancer development
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The role of nucleotide excision repair in
cancer development
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The role of homolgue recombination repair in
cancer development
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RPAIR SYSTEM GENES NEOPLASM
Mismatch repair MSH2
MLH1
MSH6
Colorectal-, ovarium-, endometrium-,
stomach cancer
Nucleotide excision repair XPA
XPC
XPG
Basocellular-, planocellular
carcinoma, melanoma
Homolog recombination repair BRCA1
BRCA2
ATM
Breast-, ovarium-, prostata carcinoma
Breast-, ovarium-, pancreas, stomach
carcinoma, melanoma
Ataxia teleangiectasia, breast
carcinoma, different sporadic
neoplasms
The role of DNA repair gene mutations
in cancer development
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Molecular mechanisms involved into
cancer development
Genetic alterations
• Oncogenes
• Tumor suppressor genes
• DNS repair genes
• Telomer and telomerase
Epigenetic alterations
• DNA-methylation
• Micro-RNS expression
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The role of telomer and telomerase in
cancer development
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Molecular mechanisms involved into
cancer development
Genetic alterations
• Oncogenes
• Tumor suppressor genes
• DNS repair genes
• Telomer and telomerase
Epigenetic alterations
• DNA-methylation
• Micro-RNS expression
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Molecular mechanisms involved into
cancer development
Genetic alterations
• Oncogenes
• Tumor suppressor genes
• DNS repair genes
• Telomer and telomerase
Epigenetic alterations
• DNA-methylation
• Micro-RNS expression
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Hipermetiláció szerpe a daganatok
kialakulásában
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GENE NEOPLASM
hMLH1 Stomach-, colorectali-, ovariumcarcinoma
APC Colorectal carcinoma
ARF Colorectal carcinoma
RB Retinoblastoma
CDKN2B Leukaemia
CDKN2A Different neoplasmsípusok
VHL Renal cell carcinoma
p16INK4A Colorectal-, urinary bladder-, oesophagus-, lung carcinoma, lymphoma
BRCA1 Breast-, ovarium carcinoma
Frequently hypermethylated genes in
different cancers
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Molecular mechanisms involved into
cancer development
Genetic alterations
• Oncogenes
• Tumor suppressor genes
• DNS repair genes
• Telomer and telomerase
Epigenetic alterations
• DNA-methylation
• Micro-RNS expression
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Ribosoma Tumorsuppressorgén Ribosoma Oncogén
The role of miRNS in the development of cancer
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miRNA type miRNA Neoplasm
Onkogene miRNA miR-17-92 Lung cancer
miR-372-373 Testis germinal tumors
miR-21 Glioblastoma, breast cancer
miR-155 Breast-, colon-, lung cancer,B-cell
lymphoma
miR-146 Breast-, pancreas-, prostate cancer
miR-121,122 Papillary thyroid cancer
Tumor suppressor miRNA miR-127 Urinary bladder-, prostatecancer
miR-15a CLL
miR-145 Colon-, breast cancer
Let-7 Related to prognosis of lung cancer
The role of miRNS in the development of cancer
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Multistep genetic alteration in cancer development