NEOPLASIA

Dr. HUDA
CIMS MULTAN

Dr. Huda
NEOPLASIA
 is an abnormal mass of tissue,
 the growth of which is uncoordinated with that of
normal tissues,
 and that persists in the same excessive manner
after the cessation of the stimulus which evoked
the change“
 With the loss of responsiveness to normal growth
controls
 MOLECULAR BASIS
OF CANCER
NON-lethal genetic damage
A tumor is formed by the clonal
expansion of a single precursor cell
(monoclonal)
Four classes of normal regulatory
genes
 PROTO-oncogenes
 Oncogenes Oncoproteins
 DNA repair genes
 Apoptosis genes

Carcinogenesis is a multistep process

CARCINOGENESIS IS
“MULTISTEP”
 NO single oncogene causes cancer


BOTH several oncogenes AND several
tumor suppressor genes must be involved
 Gatekeeper/Caretaker concept

Gatekeepers: ONCOGENES and TUMOR

SUPPRESSOR GENES
Caretakers: DNA REPAIR GENES
 Tumor “PROGRESSION”
 ANGIOGENESIS
 HETEROGENEITY from original single cell
CARCINOGENESIS:
THE USUAL (3) SUSPECTS
Initiation/Promotion concept:
 BOTH initiators AND promotors are needed
 NEITHER can cause cancer by itself

INITIATORS (carcinogens) cause MUTATIONS

 PROMOTORS are NOT carcinogenic by themselves, and
MUST take effect AFTER initiation, NOT before
PROMOTORS enhance the proliferation of
initiated cells
ONCOGENES & TUMOR
SUPPRESSOR GENES
Oncogenes :
Genes promoting autonomous cell
growth

Protooncogenes :
Unmutated cellular counterpart of gene
state
CAUSES OF CANCER

 Most cancer arises as the result of somatic

mutations in the genome resulting from:
 Chance (ie, we don’t know)
 Environmental factors – chemical, radiation,
viruses
 Ageing

 Inherited cancer syndromes- defect in

germline DNA
 Genetic alterations:
Mutations

 Epigenetic abberations:
.Alterations other than DNA mutations
.DNA methylation; Tumor suppressor genes;
.Histone modifications; Oncogene
.Alters genes expression
.Lineage commitment and differentiation
.Reversible by drugs; Therapeutic role
GENETIC ALTERATIONS
Nonlethal genetic damage:
 Initial mutation.
 Inherited (germline mutation) or acquired
(environmental factors).
Clonal expansion:
 Progeny of a single precursor cell
 Mutations are heritable and tumor specific;

- Point mutations
- Translocations
- Deletion/Addition
 Regulatory Genes:
 Proto-oncogenes

 Tumor suppressor genes

 Apoptosis genes

 DNA repair genes

Gain/Loss of functionMutator
phenotypeGenomic instability
 Stepwise acquisition of complementary mutations:
 Driver mutations;

- Initiating mutations
- Additional driver mutations
 Loss of function mutations;

- Genomic instability
.Driver mutations .Passenger mutations
ONCOGENES
AreMUTATIONS of NORMAL genes
(PROTO-oncogenes)
Growth Factors
Growth Factor Receptors
Signal Transduction Proteins (RAS)
Nuclear Regulatory Proteins
Cell Cycle Regulators
Oncogenes code for  Oncoproteins
Normal cell growth :

GF  GFR  Signal transduction

protein  Signal

transmission  Additional affecter

proteins/2nd messenger

Cascade of signal transduction

molecules (RAS, RAF,

MAPK, P13K)  Nuclear regulatory

protein  DNA
 PROTO- Mode of Associated Human
Category Oncogene Activation Tumor
GFs
PDGF-β chain SIS Overexpression Astrocytoma

Osteosarcoma
Fibroblast HST-1 Overexpression Stomach cancer
growth factors
INT-2 Amplification Bladder cancer

Breast cancer
Melanoma
TGFα TGFα Overexpression Astrocytomas

Hepatocellular
carcinomas
HGF HGF Overexpression Thyroid cancer
 PROTO- Mode of Associated Human
Category Oncogene Activation Tumor
Signal
Transduction
Proteins
GTP-binding K-RAS Point mutation Colon, lung, and pancreatic
tumors
H-RAS Point mutation Bladder and kidney tumors
N-RAS Point mutation Melanomas, hematologic
malignancies
Nonreceptor ABL Translocation Chronic myeloid leukemia
tyrosine kinase
Acute lymphoblastic leukemia
RAS signal BRAF Point mutation Melanomas
transduction
WNT signal β-catenin Point mutation Hepatoblastomas,
transduction hepatocellular carcinoma
 Mode of
PROTO- Activation Associated Human
Category Oncogene Tumor
Nuclear
Regulatory
Proteins
Transcrip. C-MYC Translocation Burkitt lymphoma
activators
N-MYC Amplification Neuroblastoma,
small cell
carcinoma of lung
L-MYC Amplification Small cell
carcinoma of lung
MYC
Encodes for transcription
factors
Also involved with
apoptosis
P53 AND RAS
p53 RAS
 Activates DNA  H, N, K, etc., varieties
repair proteins  Single most common

 Sentinel of G1/S abnormality of

dominant oncogenes
transition in human tumors
 Initiates apoptosis  Present in about 1/3
 Mutated in more of all human cancers
than 50% of all
human cancers
CHROMOSOM AL INSTABI LITY
TRANSLOCATIONS
 AMPLIFICATIONS
 Double minutes and homogenously staining
regions (HSR) are the cytogenetic hallmarks
of genomic amplification in cancer.
Point mutations
- RAS:
 . Most common (15-20%)
 . H,K,N
 . Pancr.
adenoCA(90%),Melanomas(60%)

- JAK2:
 . Myeloproliferative disorders
Tumor suppressor
genes:
-Inhibit cell growth
-RB gene was the first to be discovered
.13q14
.“Two-hit” hypothesis; two mutations involving both
alleles
.Governor of proliferation
.Role in cellular differentiation
.Key negative regulator of G1/S; inactivated by
hyperphosphorylation
.Inactivated in most tumors
(Retinoblastoma,Osteosarcoma,Carcinoma
Lung,Breast,Bladder)
 P53:
17p13.1
Guardian of the genome; senses DNA damage
slows cycle
Functions:
 Regulate cell cycle progression
 DNA repair
 Cellular senescence
 Apoptosis
-Majority of cancers (Carcinoma Lung,Colon,Breast)
-Acquired somatic mutations in majority
-Inherited less commonly (Li Fraumeni syndrome);25
fold^
THANKYOU