Neoplasia

Neoplasia

Nomenclature
Nomenclature

Benignvs.
vs.Malignant
Malignant
Benign
tumors
tumors

Epidemiology
Epidemiology

Molecularbasis
basis
Molecular

Oncogenes
Oncogenes

ApoptosisRegulating
Regulating
Apoptosis
Genes
Genes

DNARepair
Repairgenes
genes
DNA

Stepsinin
Steps
Carcinogenesis
Carcinogenesis

Karyotypicchanges
changes
Karyotypic

Tumorgrowth
growth
Tumor

GeneticsofofMetastases
Metastases
Genetics

Carcinogens
Carcinogens

Moleculardiagnosis
diagnosis
Molecular

Tumormarkers
markers
Tumor

Neoplasia is the result of:

1. Non-lethal cellular damage
2. # one target Certain genes
3. A Multi step Process
Protooncogenes Oncogenes
Retroviruses (called acute transforming viruses) = V-onc
Contain unique transforming sequences v-onc
Cause rapid induction of tumors in animals
All v-onc genes have normal cellular homologs
Insertion mutagenesis= C-onc

Insert a slow transforming virus next to a proto-oncogene in a normal cell

Cellular oncogenes (c-onc) induce a structural change in the cellular gene

Protooncogenes & Oncogenes

Protooncogenes

Oncogenes

Proteins

oncoprotein
Growth Factors
(Hormones etc.)

Normal Growth

No need of Growth Factors

Malignant Growth

Oncoprotein
Oncoproteinsimilar
similarfunctions
functionsas
astheir
theirnormal
normalcounterparts
counterparts
but
but make
makecells
cellsself-sufficient
self-sufficientto
togrow
grow

Normal Cellular counterpart of Genes Homologous to Oncogenes

1. Growth Factors
2. Growth Factor Receptors
3. G Proteins
4. Kinases Tyrosine & Cyclin dependent (major ones)
5. Gene Regulatory Phosphoprotein
6. Transcription
1
2
3

4
6

1. Oncogenes :Growth Factors

Type

Mechanism

Associated tumors

1. PDGF- CHAIN

over expression

astrocytoma and
Osteosarcoma

2. TGF- with EGF

cause over expression of

growth factor genes

Astrocytomas (TGF-)

3. HGF ( its receptorc-MET)

carcinomas of the
thyroid

4. FGF

Two Proto - oncogenes

HST 1 stomach cancer
INT 2bladder, breast,
and melanoma

Protooncogenes & Oncogenes

2. Growth Factor receptors (GFR) as oncogenes
Mechanism

Mutant GFR are in state of persistent dimerization & activation without

binding to GF

deliver continuous mitogenic signals to the cell

RET proto-oncogene

Neurotrophic factor

normally expressed in C cells of the thyroid, adrenal medulla, and parathyroid

cell precursors

Mutations MEN types 2A and 2B and familial Medullary thyroid

carcinoma

Point mutations in the RET protooncogene

In extra cellular domain MEN 2A
In cytoplasmic catalytic domain MEN 2B
C-erb B2 (EGF-R2)

Amplified in carcinomas of breast, ovary

Protooncogenes & Oncogenes

3. Signal- transducing proteins Oncogenes
point mutation of GTP-BINDING RAS proto-oncogene

Found in approximately 10-20% of all human tumors

single MC abnormality of dominant oncogenes in human tumors

Related to TGF, PDGF, and CSF-1
Also related to CDKs in regulation of cell cycle
Non receptor-associated tyrosine kinases

c-abl gene of ch.9 translocated & fused with bcr gene ch. 22 = potent
tyrosine kinase activity ( CML, AML)
4. Transcription proteins Oncogenes

Myc MC involved in human tumors

Others Myb, Jun, Fos

Oncogenic versions of myc gene

Over expression= sustained transcription & neoplastic transformation

Translocation =Seen in Burkitt lymphoma

Amplification =breast, colon, lung & other Ca.

N-myc amplification =in Neuroblastomas and small cell cancers of lung
L-myc amplification=Seen in small cell cancer of the lung

5. Cyclin D genes changes =Seen in mantle cell lymphoma, breast, liver and
esophagus cancers
6. Mutation of CDK4 = in melanoma, sarcomas, and Glioblastoma