KARSINOGENESIS

SASARAN GENETIK KARSINOGENESISSASARAN GENETIK KARSINOGENESIS

Bahan Bahan Fisiko-kimiaFisiko-kimia

VirusVirusonkogenikonkogenik

Sasaran utama:Sasaran utama:Mutasi DNA/gen regulatorMutasi DNA/gen regulator

siklus /pertumbuhan siklus /pertumbuhan selsel

TRANSFORMASI SELTRANSFORMASI SEL

Faktor endogenFaktor endogenOxidant stressOxidant stress

ONKOGENESISONKOGENESIS

Growth promotingGrowth promotingoncogenesoncogenes

Tumor suppressorTumor suppressorgenesgenes

TransformationTransformationUncontrolled growth,Uncontrolled growth,Abn biol behaviourAbn biol behaviourMaturation arrestMaturation arrest

Abnormal diffAbnormal diff

Activation/Activation/amplificationamplification

MutationsMutations

InactivationInactivation

MutationsMutations

CONTOH PERUBAHAN GENETIK DAN EPIGENETIK PADA KARSINOGENESISPerubahan Gen terkena Akibat Jenis

kankerTranslokasi bcr dan abl Fusion protein CML & ALL

Homoz deletion NF1 Deregulated p21 Neurofibrosarc

Frameshift mut APC Disfungsi TSG Kolorektal

Amplifikasi gen EGFR Aktivasi autokrin Banyak

Substitusi single base

P53 Kontrol checkpoint hilang

Banyak

Polimorf minisa-telite

H-ras Predisposisi Ca Banyak

Simple repeat polymorh, hyper mutability

hMSH2 dan hMLH1

Instabilitas genetik

Kanker kolon SCLL

Weinstein 1995

EVOLUSI MULTISTEP KANKER KOLONEVOLUSI MULTISTEP KANKER KOLON

Epitel normal

Hiperproliferasi

Karsinoma

Late adenoma

Metastasis

Earlyadenoma

Intermedadenoma

KromosomKelainanGen

5qLossAPC

HipometilasiDNA

12pAktivasi/mutasiK-ras

18q, loss, DCC

17p, mutasi, p53

Kelainan lain

Mism

atch rep

air

DAMPAK BERBAGAI KARSINOGENDAMPAK BERBAGAI KARSINOGEN

Bahan FisikaBahan FisikaVirus onkogenikVirus onkogenik

Hbg dose-responseHbg dose-responseMutasi DNAMutasi DNAAktivasi transduksiAktivasi transduksisinyalsinyalInisiator & PromoterInisiator & Promoter

Radiasi:Ionizing, UVDose dependenceTissue specificKematian selMutasi gen spesifikAktivasi transduksisinyal

2 golongan virus:2 golongan virus:Virus DNA & retrovirusVirus DNA & retrovirusIntegrasi DNA/RNAIntegrasi DNA/RNAvirus dg gen hostvirus dg gen hostAktivasi ekspresiAktivasi ekspresionkogenonkogenDisrupsi berbagai genDisrupsi berbagai genpejamu a.l. TSGpejamu a.l. TSG

Bahan kimiaBahan kimia

MULTISTEP CARCINOGENESISMULTISTEP CARCINOGENESIS

Environment CarcinogenCarcinogen

Electroph interm

metabolism Excretion

detoxification

detoxification

Binding to DNA RNA, protein

Normal cellDNA repair

Cell death

Permanent DNA lesion

DNA replication

Preneoplastic cells

Neoplastic cells

? ?

Initiation

Promotionand

ProgressionMultiple factorsMultiple stagesMultiple genetic targets

Staging system

1. Anatomical Staging System

2. Functional Staging System

3. Combined staging System

4. Multivariate Regression Algorithm

Modalitas terapi pada kanker

1. Kemoterapi

2. Radioterapi

3. Terapi pembedahan

4. Bioterapi (BRM’s)

5. Cangkok sumsum tulang

6. Gene replacement