Lec 2 - Molecular Basis of Cancer Flashcards
AUCOM
change in morphological appearance of a cell is due to ______ change
Molecular
Each cancer must result from accumulations of ________
multiple mutations
Morphological appearance means
phenotype
Molecular change means
genotype
change in genotype results in ______
change in phenotype
Morphologic appearance: Normal epithelium
Molecular change:
Loss/mutation in APC locus on chromosome 5q
Morphologic appearance: hyperproliferative epithelium
Molecular change:
loss of DNA methylation
Morphologic appearance: early adenoma
Molecular change:
mutation of RAS gene on chromosome 12q
Morphologic appearance: intermediate adenoma
Molecular change:
loss of TSG on chromosome 18p
Morphologic appearance: late adenoma
Molecular change:
loss of RAS gene on chromosome 17q
Molecular change: mutation/loss in APC locus on c/5q
Morphologic appearance:
normal epithelium
Molecular change: loss of DNA methylation
Morphologic appearance:
hyperproliferative epithelium
Molecular change: mutation of RAS on c/12p
Morphologic appearance:
early adenoma
Molecular change: loss of TSG on c/18q
Morphologic appearance:
intermediate adenoma
Molecular change: loss of RAS gene on c/17p
Morphologic appearance:
late adenoma
irreversible alteration of DNA
mutation
cause of mutation
inherited in germ line, or
acquired (radiation, chemicals, virus, etc..)
are most malignant tumors monoclonal or polyclonal
monoclonal
result from transformation of a single cells
monoclonal
What are the molecular basis of cancer?
- Mutation
- involvement of cell replication and death regulatory genes
- tumors result from clonal expansion of a single precursor cell
- Progression of tumor cells inducing mew features (heterogenous)
Normal regulatory genes involved in cell replication & death
- Growth promoting genes (encode GF, GFR, proteins of cell cycle)
- Tumor suppressor genes
- Genes regulating apoptosis
- Genes of DNA repair enzyme (Repair mutations before progression)
______ are cancer inducing genes derived from cellular genes called protooncogenes.
Oncogenes
he mutant alleles of protooncogenes are called ______
oncogenes
_______ are dominant because mutation of a single allele can lead to cellular transformation
oncogenes
Protooncogene: PDGF
oncogene:
SIS
Protooncogene: EGF-R
oncogene:
ERB-B2
Protooncogene: Tyrosine kinase
oncogene:
ABL
(Signal transduction)
Protooncogene: transcription activator
oncogene:
MYC
(DNA binding protein)
Methods of gene activation
1-Point mutation
2-Chromosomal translocation.
3-Gene amplification.
4-Gene deletion
gene activation results in
change in structure or quantity of gene product (change in functional proteins)
give examples of 2 tumors produced by gene activation via Chromosomal Translocation
Burkitt lymphoma and
Chronic myelogenous leukemia.
Explain the chromosomal translocation & associated oncogenes in chronic myelogenous leukemia
Chromosomal Translocation in Chronic Myelogenous Leukemia (CML):
Chronic myelogenous leukemia is often characterized by a specific chromosomal translocation known as the Philadelphia chromosome. Parts of chromosome 9 and chromosome 22 exchange places, resulting in the formation of the Philadelphia (Ph) chromosome.
Associated Oncogene:
The key oncogene involved in the Philadelphia chromosome is called BCR-ABL1. This fusion gene is created when a portion of the ABL gene from chromosome 9 fuses with a portion of the BCR gene on chromosome 22. The BCR-ABL1 gene produces a protein with abnormal tyrosine kinase activity, leading to uncontrolled cell growth and the development of chronic myelogenous leukemia.
Explain the chromosomal translocation & associated oncogenes in Burkitt Lymphoma
Chromosomal Translocation in Burkitt Lymphoma:
Burkitt lymphoma is often characterized by a specific chromosomal translocation known as t(8;14). This means that a portion of chromosome 8 breaks off and attaches itself to chromosome 14. This translocation leads to the activation of oncogenes.
Associated Oncogenes:
The translocation involves the MYC oncogene, which is normally located on chromosome 8. When it fuses with the immunoglobulin heavy chain gene (IGH) on chromosome 14 due to the translocation, it results in the overexpression of MYC. This overexpression is a key factor in the rapid and uncontrolled division of B cells, leading to the development of Burkitt lymphoma.
Give an example of a tumor produced by gene activation via Gene Amplification
Neuroblastoma
Gene involved in Burkkit’s Lymphoma
MYC gene
Gene involved in chronic myeloid lymphoma
BCR-ABL1 gene
Explain gene amplification of N-MYC gene in Neuroblastoma
N-MYC present normally on 2p, becomes amplified & seen either as extra chromosomal double minutes or as a chromosomally integrated homogenous staining region (HSR)
What are the changes necessary for malignant phenotype?
SIA-GRAM
- Self-sufficiency in growth signals (Oncogenes).
- Insensitivity to growth inhibitory signals (Suppressors).
- Evasion of apoptosis (programmed cell death :i.e. immortality of neoplastic cells)
- Genetic instability (Accumulation of mutation Enabler of malignancy), due to defect in DNA repair.
- Limitless replication potential (Telomeres determine the life of individual cell) i.e overcoming cellular senescence, due to telomerase expression .
- Development of Sustained angiogenesis.
- Ability to invade & metastasize (new features acquired during new mutations ).
Genes that promote autonomous cell growth in cancer cells in absence of normal promoting signals. They are usually dominant genes
Oncogenes
Oncogenes are classified by
site of action
Oncogenes include:
- growth factors
- growth factor receptors
- signal transducing proteins
- nuclear transcription factors
- cell cycle proteins (cyclins and CDKs)
- antiapoptotic proteins
Cancer cells acquire growth self-sufficiency by:
- Ability to synthesize the same growth factors to which they are responsive to (autocrine)
- Overexpression of growth factor genes
what are the 2 ways mutant receptor proteins work?
A)) Continuous mitogenic signals to cells, even in the absence of GF in environment.
B)) Normal but overexpressed receptors that are hypersensitive to GF. (amplifications)
Epidermal GF receptor families:
- ERBB1 in 80% of sq. CA lung
- ERBB2 ( HER 2 ) in 25-30% of breast & ovarian carcinoma
ERBB1 is expressed in
80% of sq. CA lung
ERBB2 ( HER 2 ) is expressed in
25-30% of breast & ovarian carcinomas
overexpression growth factor receptor leads to
constitutive tyrosine kinase activity (mitogenic signals)
cells become hypersensitive with a small amount of GF
Breast carcinoma responds to
Herceptin therapy (Anti Her-r antibodies)
RAS action
Active RAS activates down-stream regulators of proliferation (kinase mitogenic cascade) which flood the nucleus with signals for cell proliferation.
________ in RAS are present in +30% of all cancers, specially pancreatic & GIT cancer
Point mutations
A proto-oncogene that has tyrosine kinase activity and is located in cytoplasm and effect on nucleus where it promotes apoptosis of cells that suffer DNA damage .
ABL
action of ABL
Proliferation + Absent Apoptosis.
Gleevec - imanitib mesylate is a drug that inhibits:
ABL-BCR Kinase
ABL-BCR Kinase is inhibited by (drug)
Gleevec - imantinib mesylate
gene mutated in: Burkitt’s lymphoma
C-MYC
gene mutated in: neuroblastoma
N-MYC
gene mutated in: CA of breast, lung, colon
L-MYC
CDKs at G1 > S phase checkpoint
CDK4 & CDK6
Activity of CDK/Cyclin is regulated by
CKD inhibitors
Overexpression of cyclin D in:
breast, liver, & esophageal cancers
Amplification of CDK4 gene in:
melanoma, sarcomas, glioblastoma
P16: Inhibits Rb phosphorylation by______ leading to ______
blocking Cyclin D-CDK4 complex.
inhibition of cell growth
P14ARF : Activate P53 pathway by ______ leading to _______
inhibiting MDM2.
increased apoptosis
P16 & P14 are silenced/activated in many malignancies?
silenced
Growth inhibitory pathway is achieved by:
Rbgene
PT 53
TGF-beta
APC
TGF-beta function
Block GF signals
Rb gene regulates
cell cycle
P53 Regulate
cycle & apoptosis:
APC function
regulates beta-catenin
_______ gene is mutated in colon carcinoma
APC
_________ genes are recessive genes which may be lost in familial or sporadic cases or may become mutated
Cancer/tumor suppressor genes
_______is cytoplasmic protein that regulates intracellular level of beta-catenin and it exerts an antiproliferative effect
APC gene
a transcription activation factor (TcF) of growth promoting genes ( CyclinD1, MYC).
beta-catenin
Function of Rb gene
prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, Rb is phosphorylated to pRb, leading to the inactivation of the activity of Rb.
Normally, Rb phosphorylation allows cells to enter into the cell cycle. Rb role is regulating what part of the cell cycle?
G1»_space; S check point of cell cycle.
T/F
Rb exists in active nonphosphorylated & inactive phosphorylated forms.
True
An autosomal recessive hereditary disease. May be sporadic.
Retinoblastoma
how many alleles are required to be mutant for retinoblastoma to occur?
two alleles in 13q14 (recessive)
mutant alleles are required for retinoblastoma to form
two alleles in 13q14
Loss of normal cell cycle control is central to malignant transformation & at least one of the following is mutated in most human cancers :
- Cyclin D
- CDK 2, CDK 4, CDK 6
- CDK inhibitors
- RB
T/F
Many virus (HPV) bind to the hypo-phosphorylated Rb. This leads to diminished cell proliferation.
False
hypo-phosphorylated Rb = Active Rb. If a virus binds to it, Rb becomes inactive and proliferation increases.
_______ is a tumor suppressor gene , play important role as guardian of the genome
PT53
normal half life of P53
normally present in low levels with short half life ( 20 minutes )
in stressed, healthy cells, the half life of P53 increases or decreases?
In stressed, healthy cells, P53 undergo post transcreptional modefication that release it from MDM2 and increase half life
what happens to P53 in stressful situations in healthy cells?
In stressed, healthy cells, P53 undergoes post transcreptional modefication that release it from MDM2 and increase half life
T/F?
Non functioning mutants of PT53 have a long half life & accumulate in cell
True
PT 53 effects
it has an antiproliferative effect & regulates apoptosis.
Acquired mutation of P53 leads to
many cancers : e.g. colon, breast, lung , leukemia etc…
Inherited mutation of P53 leads to
cancers like Li -Fraumeni S. sarcoma, leukemia, breast & brain, etc…
P21(=CDK inhibitor) function
Arrest cell at G1
GADD45 gene function
DNA repair
BAX gene function
apoptosis
BAX,
BCL-2,
BCL-x,
BAD
Apoptosis Genes
BCL-2 function
prevents apoptosis
how is BCL-2 (antiapoptotic gene) activated?
Activated by translocation (18:14 )
leads to low grade B cell Lymphoma .
DNA Repair Genes include
- Nucleotide excision repair genes
- DNA Mismatch repair genes
genes that repair damage caused by U-V light. Defect in the genes that encode certain enzymes involved in DNA synthesis
Nucleotide excision repair genes
genes that repair errors in pairing of nucleotides during cell division . e.g. G+T instead of A+T
DNA Mismatch repair genes
These genes are not oncogenic but allow mutation in other genes in normal cell cycle
Hereditary Nonpolyposis Colonic CA.) (HNPCC).
important in repairing breaks in DNA but are rarely inactivated in sporadic cases.
BRCA1 , BRCA2
BRCA-1 repairs DNA in
In familial breast cancer & ovarian CA
BRCA-2 repairs DNA in
in breast CA in both sexes,
prostate, ovary, pancreas, stomach CA
what’s ‘senescence’?
After a certain number of divisions, the chromosomes can become damaged to the point that the cells can’t divide anymore — a state called senescence.
Cancer cells often avoid senescence or cell death by _______
by maintaining their telomeres despite repeated cell divisions, via telomerase enzyme.
how can cancer cells maintain their telomeres despite repeated cell divisions?
This is possible because the cancer cells activate an enzyme called telomerase, which adds genetic units onto the telomeres to prevent them from shortening.
As a result, cancer cells essentially become immortal.
