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
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NON-lethal genetic damage A tumor is formed by the clonal expansion of a single precursor cell (monoclonal) Four classes of normal regulatory genes.
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MOLECULAR BASISof 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
Carcinogenesis is a multistep process at both the phenotypic and the genetic levels.
It starts with a genetic damage: Environmental
Chemical Radiation Viral
Inhereted
Carcinogenesis
Genetic damage lead to “ mutation” single cell which has the genetic damage
undergoes neoplastic prliferation ( clonal expansion) forming the tumor mass
TRANSFORMATION &PROGRESSION
Self-sufficiency in growth signals Insensitivity to growth-inhibiting
signals Evasion of apoptosis Defects in DNA repair: “Spell checker” Limitless replicative potential:
Translocated in 90% of all Burkitt’s lymphoma cases 90% of gynecological cancers 80% of breast cancers 70% of colon cancers
Contributes to more than 70,000 cancer deaths annually in the U.S.
REMEMBER
Translocation in Burkitt lymphoma, a B cell tumor. (t9:22)
Amplified in breast, colon, lung, and many other cancers;
Amplified in N-MYC NEUROBLASTOMAS L-MYC small cell cancers of
lung.
Tumor supressor gene
. Tumor suppressor were originally identified as inherited mutations that confer a
predisposition to cancer (familial form).
Inactivation of tumor suppressors can occur Sporadically -sequential inactivation of both alleles in somatic
cells You may hear the term haploinsufficiency , which refers to inactivation of a single allele contributing to malignancy. -usually not the initiating event, but exacerbating. Viral inactivation -HPV expresses proteins that inhibit Rb and p53
It is a tumor suppressor gene It is located on chromosome 13 It regulates G1 /S transition
phase. It occurs in active
hypophosphorylated and inactive hyperphosphorylaed state
RB gene
A Loss of RB function confers a predisposition to retinoblastoma.
occurs in both the familial form (early onset)
and sporadic form.
Retinoblastoma
Red reflex Leukocoria
Knudson, in 1974, proposed two-hit hypothesis, which in molecular terms can be stated as follows:
1. Two mutations (hits) are required to produce retinoblastoma. Both of the normal
alleles of the RB locus must be inactivated (hence the two hits) for the development of retinoblastoma.
2.In familial cases, children inherit one defective copy of the RB gene in the germ line; the other copy is normal. Retinoblastoma develops when the normal RB gene is
lost in retinoblasts as a result of somatic mutation.
3.In sporadic cases, both normal RB alleles are lost by somatic mutation in one of the retinoblasts.
The end result is the same: a retinal cell that has lost both of the
normal copies of the RB gene becomes cancerous.
Why Retinoblastoma is autosomal dominant?
Retinoblastoma families only a single somatic mutation is required for expression of the disease,.
Loss of heterozygosity(LOH)
In hereditary retinoblastoma, an affected child inherits one defective Rb allele together with one normal gene. This is heterozygous state.
It is not associated with changes in the retina because 50% of the Rb gene product is sufficient to prevent
the development of retinoblastoma. If the remaining normal Rb allele is inactivated by
deletion or mutation, the loss of its suppressor function leads to the appearance of a neoplasm.
This genetic process is referred to as loss of heterozygosity.
The importance of Rb lies in its regulation of
the G1/S checkpoint
loss of normal cell cycle control leads to malignant transformation
the four key regulators of the cell cycle (CDKN2A, cyclin D,CDK4, Rb) is mutated in most human cancers.
Functional deletion of RB
Human papillomavirus(HPV) produce E7 protein and the protein E7 binds to the hypophosphorylated form of Rb in place of E2F leading to uncontrolled growth.
SPORADIC (Non-hereditary)
Unilateral, unifocal. 60% of all cases. Present later. Children of the
affected are normal. Chromosomal
anomaly is a somatic mutation. Relatives have a low
risk of RB development
FAMILIAL (Hereditary)
85% bilateral, multifocal. 40% % of all cases. Present earlier. Children of the affected
have 45% chance of inheritance.
Chromosomal anomaly is a Germline mutation.
Autosomal dominant with high penetrance.
The median age at presentation is 2 years, although the tumor may be present at birth.
Clinical features poor vision,
strabismus, A whitish hue to
the pupil ("cat's eye reflex"),
pain and tenderness in the eye.
P53
The TP53 gene which encodes p53 resides on the short arm of chromosome 17.
In healthy unstressed cells,
p53 is short half life (20 min)
It undergo destruction by MDM2.
IT HAS DIFFERENT NAMES “GUARDIAN OF THE
GENOME.” GATE KEEPER.
MOLECULAR POLICE MAN.
When cell is stressed, When ever there is a DNA Damage ATM (ataxia telangiectasia mutated) are
activated. These activated complexes release P53
from MDM2 and increase its half-life and
enhance its ability to drive the transcription of target genes. Hundreds of genes whose transcription is triggered by p53 have been found.
cell death (termed apoptosis). 4.p53 plays a central role in
maintaining the integrity of the genome.
P53 is activated by the following
.DNA damage by irradiation, chemicals,
uv light and Free radicle injury and senescence.
Inactivation of P53
Point mutationsMDM2 –degrade P53E6 protein-From HPV
p53-mediated cell cycle arrest in response to DNA damage in
The late G1 phase and is caused mainly by p53-dependent
transcription of the CDKI gene CDKN1A (p21)belongs to KIP/CIP group of CDKI.
P53 induces expression of DNA damage repair genes to reapir the damaged DNA.
p53-induced apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against neoplastic transformation by pro-apoptotic genes such as BAX.
70% of human cancers have a defect in P53 gene, Most commonly in Breast , colon and lung
cancer
Li-Fraumeni syndrome.
Less commonly, some patients inherit a mutant TP53 allele The disease is called the
Li-Fraumeni syndrome.
patients with Li-Fraumeni syndrome develop tumors at a younger age and may develop multiple primary tumors.
25-fold greater chance of developing a malignant tumor by age 50 in a person with mutant single allele.
sarcomas, breast cancer, leukemia, brain tumors, and
carcinomas of the adrenal cortex. patients with Li-Fraumeni syndrome develop tumors at a younger
age and may develop multiple primary tumors.
1: Failure of DNA Repair (acquired)
Normal function of p53 is to upregulate activity of which 2 genes to allow repair of DNA?
p21
GADD45
Summary
p53 inhibits G1 progression only in response to DNA damage
-normally p53 is very unstable, due to proteolytic degradation triggered by mdm2
.p53 is phosphorylated in response to DNA damage; mdm2 no longer binds p53
-p53 upregulates expression of p21, which in turn inhibits G1/S CDKs.
c. In response to excessive DNA damage, p53 can trigger apoptosis
Tumor (really “GROWTH”) suppressor genes
TGF-β COLON E-cadherin STOMACH NF-1,2 NEURAL TUMORS APC/β-cadherin GI, MELANOMA SMADs GI RB RETINOBLASTOMA P53 EVERYTHING!! WT-1 WILMS TUMOR p16 (INK4a) GI, BREAST BRCA-1,2 BREAST KLF6 PROSTATE
Evasion of APOPTOSIS
BCL-2 p53 MYC
DNA REPAIR GENE DEFECTS
DNA repair is like a spell checker HNPCC (Hereditary Non-Polyposis
Brain Neuroblastoma-Liver & Bone Less common sites
of metastases include skin, muscle thyroid,
breast….etc.
CA LUNG-Smoking CA CERVIX-Sexual transmission of HPV CA BLADDER -Rubber Industry CA LIVER --Aflatoxin & HBV infection CA THYROID-Radiation ANGIOSARCOMA of Liver-Plastic(PVC) MESOTHELIOMA -Asbestos
Effects of tumor on body
Location of tumor is of importance 1- Mass effect by pressing on vital areas e.g. airway, intestine , BV, brain, nerve obstruction, infarction , paralysis…etc 2- Local destruction of epithelial surface
or BV ulceration , bleeding , infection3-
Hormonal activity
CANCER CACHEXIA
Wasting syndrome characterized by anorexia , loss of body fat & weight, with marked weakness, anemia & fever.
Reduced food intake but high metabolic rate
Possibly due to release of cytokines by tumor cells & macrophages
Para neoplastic syndrome
Systemic symptoms that can't be explained by effects of local or distant spread of tumor
or hormones appropriate to tumor tissue. Due to ectopic production of hormones or
other factors They may precede the tumor or mimic
metastases They occur in about10%-15%of malignant
tumors.
DIAGNOSIS
History & clinical examination Radiographic techniques 1- X ray 2CT scan 3- MRI 4-Ultrasound 5-Laboratory tests : general & specialized
This is very important as many cancers a recurable if they are diagnosed early.
Specific symptoms should be followed upe.g. Abnormal bleeding Change of voice Change in a nevus Abnormal lump in breast
An ulcer that does not heal……etc.
Self examination of the breast- Mammography- Serial PAP smears for the cervix- Serial sputum cytology in smokers- Serial urine cytology in some cases, e.g. workers in rubber
Screening for genetic mutations in familial cancers.
Cytological methods :
Study of cells :- Smear- FNA, Brush, Fluid tapping…etc Papanicolaou stain (PAP)often used. False(+), False (-)- A negative report
does not exclude malignancy, repeat- Advise biopsy, even if (+ )
1-Morphological Methods :
Biopsy of tissue: Needle & core biopsy , Endoscopic Biopsy, or open surgical biopsy
Frozen Section (Rapid technique) Paraffin Section ( 36-48 hrs. or longer ) H&E, Special histochemical stains stains)
or by IMMUNOHISTOCHEMICALMethods
Tumor markers represent biochemical indicators of the presence of a tumor.
Their uses are to I - Confirm diagnosis. II -Determine the response to treatment . III - Detect early relapse. Present in serum or urine. Many are present in normal & tumor
tissue, so they are not very specific but their level is important.
Types of tumor marker
Hormones Human Chorionic Gonadotrophic
Hormone( HCG)Elevated levels are seen in
Pregnancy& Gestational Trophoblastic Disease
Calcitonin useful in diagnosis of some thyroid carcinomas
Oncofetal antigens
Carcinoembryonic Antigen ( CEA ) : in fetal tissue & some malignancies
Colorectal CA & Pancreatic CA Alpha Fetoprotein (AFP):Cirrhosis :
Elevated Hepatocellular carcinoma : Extremely high
ISOENZYMES
Prostatic Acid Phosphatase ( PAP ) levels seen in Metastatic prostatic
CA Useful in : Staging prostatic CA Assessment of prognosis Response to th
erapy.
Several mucins
MUC-1 in breast CA CA-125 in ovarian CA CA-19-9 in pancreatic &