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 functionMutator
phenotypeGenomic 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
