Gen trerkait kanker

Tofrizal

CARCINOGENESIS Carcinogenesis suatu proses

multistep baik pada tingkat genotip phenotypic

Dimulai dengan kerusakan genetic linkungan

Kimia Fisik radiasi biologis

Turunan

Carcinogenesis Genetic damage --> “ mutasi” single cell genetic damage -

neoplastic prliferation ( clonal expansion) massa tumor

Kesimpulan : faktor terpenting : “mutasi gen”

Carcinogenesis Target kerusakan gen untuk

karsinogenesis 4 gen regulator utama:

Growth promoting protooncogenes Protooncogene > mutasi > oncogene

Growth inhibiting (supressors) genes Genes apoptosis DNA repair genes

Carcinogenesis Perubahan fisiologis utama untuk

timbulnya fenotip ganas: Self-sufficiency sinyal pertumbuhan Insensitivitas terhadap sinyal

penghambat pertumbuhan (growth-inhibitory signals)

Lolos tehadap apoptosis Potensi replicatif yang tak terbatas angiogenesis Kemampuan invasi dan metastasis

A - Self-sufficiency sinyal pertumbuhan :

Oncogene: gen yang menimbulkan pertumbuhan autonom pada sel kanker

Berasal dari mutasi protooncogen Ciri khas : mampu meransang

pertumbuhan otonom tanpa adanya sinyal pertumbuhan normal

Oncoproteins : produk dari onkogen

Siklus sel Terikatnya growth factor pada receptor

di membran sel Activasi growth factor activasi signal-

transducing proteins Transmissi signal ke nucleus Induksi transcription DNA Entry : cell cycle cell division

1- Growth factors: Kunci : sel kanker harus mampu

mensintesa growth factors yang sama/mirip dengan growth factor normal yang ia perlukan Sarcomas ---- > TGF-a Glioblastoma-----> PDGF

2-Growth factors receptors: Receptors mutation , continous

signals to cells and uncontroled growth

Receptors overexpression over sensitive hyperresponsive terhadap kadar normal growth factors

: Epidermal Growth Factor ( EGF )

Receptor familyHER2

Amplifikasi pada ca payudara HER2 ↑ poor prognosisAnti- HER2 antibodies treatment

3- Signal-transducing proteins : Menerima sinyal dari growth factor

reseptor meneruskan ke nukleus : Gen yang terkait : golongan

RAS ABL

RAS : 30% tumor manusia mutasi RAS gene

: ca : colon . Pancreas cancers Mutasi RAS gene pling sering ditemui Mutasi pada RAS proliferasi cells

terus berlanjut

ABL gene ABL protooncogene tyrosine kinase

activity Pada : chronic myeloid leukemia

( CML ) : t( 9,22) ---ABL gene pindah dari ch. 9 ke ch.

22 Fusion dengan BCR ---> BCR-ABL BCR-ABL : tyrosine kinase acttivity ---

( oncogene)

Carcinogenesis CML patients are treated with

( Gleevec) which is inhibitor of ABL kinase

Carcinogenesis4- Nuclear transcription factors :

Mutations may affect genes that regulate transcription of DNA growth autonomy

E.g. MYC MYC protooncogene produce MYC protein

when cell receives growth signals MYC protein binds to DNA leading to

activation of growth-related genes

Normal : MYC menurun aktivitasnya saat siklus sel dimulai tapi pada tumor : MYC tetap menaik continuous proliferation

E.g. Burkitt Lymphoma ; MYC dysregulated

MYC

Cyclins5- Cyclins and cyclins- dependent

kinases (CDKs) Progresi sel berlanjut akibat

kontrolsiklis sel tidak terjadi sel masuk kesiklus selanjutnya tanpa perlu berhenti

Mutasi cyclins dan CDKs : Cyclin D genes : overexpress : breast,

esophagus hati CDK4 : amplifikasi melanoma sarcomas

Perubahan sel pada kanker :A- Self-sufficiency in growth signalsB- Insensitivity to growth-inhibitory

signalsC- Evasion of apoptosisD- Limitless replicative potentialE- Sustained angiogenesisF- Ability to invade and metastsize

2. Insensitivitas thd growth-inhibitory signals

Tumor supressor genes control : rem proliferasi sel

Mutation uncontrolled proliferation

RB, TGF-b, APC, TP53

RB ( retinoblastoma ) gene : tumor supressor gene pertama yang

ditemukan Pada retinoblastomas Tumor lain . breast ca RB gene : DNA-binding protein chromosome 13

RB gene : “ active “ , “ inactive” forms

active stop G1 to S phase pd cell cycle

Stimulus growth factors inactivasi RB gene brake off mulai cell cycle …G1 SM …lalu RB gene aktif kembali

Retinoblastoma childhood tumor Retinoblastoma : sporadic (60%) atau

familial ( 40% ) Butuh dua mutations retinoblastoma normal copies harus hilang untuk jd :

retinoblastoma

Carcinogenesis Transforming Growth Factor- b

pathway: TGF- b : inhibitor of proliferation regulate RB pathway Inactivation of TGF- b cell

proliferation Mutations TGF- b :

100% pancreatic cancers 83% colon cancers

Adenomatous Polyposis Coli – b Catenin pathway: APC : tumor supressor gene APC gene loss very common: colon

cancers colonic polyps

TP53 ( P53 ) multiple functions

Tumor suppressor gene ( anti-proliferative ) Regulates apoptosis

TP53 senses DNA damage : G1 arrest DNA repair Induksi DNA repair genes damaged DNA cannot be repaired,

TP53 to undergo apoptosis

Carcinogenesis loss of TP53, DNA damage goes

unrepaired Mutations will be fixed in the

dividing cells, leading to malignant transformation

TP53 “ guardian of the genome” 70% cancers --: defect in TP53 almost all types of cancers : e.g.

lung, colon, breast , acquired, inhereted, e.g : Li-Fraumeni

syndrome

Carcinogenesis

Main changes in the cell physiology that lead to formation of the malignant phenotype:A- Self-sufficiency in growth signalsB- Insensitivity to growth-inhibitory

signalsC- Evasion of apoptosisD- Limitless replicative potentialE- Sustained angiogenesisF- Ability to invade and metastsize

Evasion of apoptosis:

Evasion of apoptosis CD95 loss of TP53 up-regulation of

BCL2 prevent apoptosis : follicular lymphoma

Carcinogenesis Main changes in the cell physiology

that lead to formation of the malignant phenotype:A- Self-sufficiency in growth signalsB- Insensitivity to growth-inhibitory

signalsC- Evasion of apoptosisD- Limitless replicative potentialE- Sustained angiogenesisF- Ability to invade and metastsize

Limitless replicative potential : Normal: shortening of telomeres: batas

proliferasi Telomerase is active in normal stem cells but

absent in somatic cells In tumor cells : activation of the enzyme

telomerase, which can maintain normal telomere length

Carcinogenesis Main changes in the cell physiology

that lead to formation of the malignant phenotype:A- Self-sufficiency in growth signalsB- Insensitivity to growth-inhibitory

signalsC- Evasion of apoptosisD- Limitless replicative potentialE- Sustained angiogenesisF- Ability to invade and metastsize

Carcinogenesis Sustained angiogenesis

Neovascularization has two main effects: Perfusion supplies oxygen and nutrients Contoh gen : PDGF, IL-1

Angiogenesis sangat perlu untuk metastasis

blood supply Tumor-associated angiogenic factors produced by tumor cells atau oleh

inflammatory cells infiltrating the tumor e.g. macrophages

: Vascular endothelial growth factor( VEGF ) Fibroblast growth factor

Carcinogenesis Main changes in the cell physiology

that lead to formation of the malignant phenotype:A- Self-sufficiency in growth signalsB- Insensitivity to growth-inhibitory

signalsC- Evasion of apoptosisD- Limitless replicative potentialE- Sustained angiogenesisF- Ability to invade and metastsize

Carcinogenesis Ability to invade and metastsize:

Two phases : Invasion of extracellular matrix Vascular dissimenation and homing of

tumor cells

Carcinogenesis Invasion of ECM:

Malignant cells merusak underlying basement membrane

Traverse ke interstitial tissue Menembus vascular basement

membrane circulation

Invasion of the ECM has four steps:

1. Detachment of tumor cells from each other

2. Attachments of tumor cells to matrix components

3. Degradation of ECM by collagenase enzyme

4. Migration of tumor cells

Carcinogenesis Vascular dissemination and homing

of tumor cells: May form emboli Most travel as single cells Adhesion to vascular endothelium extravasation

Carcinogenesis Main changes in the cell physiology

that lead to formation of the malignant phenotype:A- Self-sufficiency in growth signalsB- Insensitivity to growth-inhibitory

signalsC- Evasion of apoptosisD- Limitless replicative potentialE- Sustained angiogenesisF- Ability to invade and metastsize