Oncopathology 1 Flashcards
……………..is a multistep process resulting from the accumulation of multiple genetic
alterations that give raise to transformed cancer cells
Carcinogenesis
are mutations that alter the function of cancer genes and
thereby contribute directly to the development or progression of cancer.
Driver mutations
are mutations that do not affect cellular behavior
Passenger mutations
Passenger mutations usually( more / less) than driver mutations ?
More
Example of Over-expression of proto-oncogenes is …..
And between which genes ?
t(8:14) in Burkitt Lymphoma
Between MYC gene (chromosome 8) and IG (chromosome14 )
BCR-ABL1 fusion gene, are characteristic of wich disease? (CML).
chronic myeloid leukemia
سرCR يعني للأبد chronic
1-Example of Creation of novel fusion proteins ?
2- It’s lead to ……
3- Between which genes?
1 -t(9:22) ABL-BCR gene Hybrid gene
2- Chronic Myeloid Leukemia
3- At chromosome 9 there is gene called ( ABL )and at chromosome 22 there is a
gene called (BCR) .
Example of Deletions of genetic lesions in cancer ?
loss of particular tumor suppressor genes
What is the common mechanism that Lead to lost tumor suppressor gene ?
one allele is lost through inactivating point mutation and the other allele is lost through deletion
Example of Gene Amplification ? And it’s disease
Example: NMYC gene in Neuroblastoma
…….is a state of number of chromosomes that is multiple of the
haploid state
Euploidy
……….is a state of number of chromosomes that is not a
multiple of the haploid state.
Aneuploidy
Aneuploidy occurs mainly from errors in……… when chromosomes separate
into two sides by the mitotic spindle.
mitosis
Aneuploidy tends to [increase/decrease] the copy number of oncogenes and
[increase /decrease] the copy number of tumor suppressor genes.
1-increase
2-decrease
Example of Aneuploidy ?
Loss of chromosome 17 results in loss of TP53 gene, an important tumor suppressor gene.
Loss of chromosome 17 results in loss of…….. an important
tumor suppressor gene.
TP53 gene
epigenetic changes include …….
The structure around the DNA
include DNA methylation and histone modification
And histone acetylation or deacetylation
(…………….) is overexpressed in most carcinomas of the lung and
head and neck
ERBB1 (or EGFR)
(………..) is overexpressed in 20% of breast cancer, due to
gene amplification
ERBB2 (or HER2)
Hb
HER2 in which cancer ?
breast cancer
ERBB1 (or EGFR) in which cancer ?
lung and head and neck
Types of genetic lesions include in the in the growth factor receptor is :
- Gene Mutations (Point mutations)
- Gene Rearrangements
- Gene Deletions
- Gene Amplification
- Aneuploidy
- Lesions affecting MicroRNA
4
Which drug can help us to block HER2 for breast cancer?
anti-HER2 antibodies (Trustuzumab)
What are the two enabling characteristics that can accelerate the acquisition of genetic and epigenetic alterations responsible for this 8 hallmarks ?
- Genomic Instability
- Tumor-promoting inflammation
………………… are Alterations in genes that regulate some or all of these cellular
functions are seen in every cancer.
Hallmarks of Cancer
How I am ?
………..hallmark originates from gain-of-function mutations that
converts proto-oncogenes to oncogenes.
Self-Sufficiency in growth signals
What are the functions of Oncoproteins ?
promote (cell growth )and (proliferation), even in the
absence of normal growth-promoting signals.
protein product of oncogenes is known as…….
Or which protein is converts proto-oncogenes to oncogenes……..
oncoproteins.
In the inactive state, RAS is bound to (GTP /GDP)
GDP
When a growth factor binds with
the receptor, it leads to activation of
………..by………… of GDP to
become…………
RAS
phosphorylation
GTP
In the active state, RAS is bound to (GTP /GDP)
GTP
Activated RAS-GTP activates several
downstream signaling proteins in
growth pathways leading to
….………….of genes responsible for cell growth
transcription
Why the activation of RAS-GTP is short-lived ?
because RAS has an intrinsic GTPase activity
What is the function of intrinsic GTPase activity?
GTP——>GDP
Where we can found the intrinsic GTPase activity?
In the RAS
Downstream Signal Transducing Proteins examples include :
4 example
include: RAS, NF1, BRAF, and ABL.
• RAS is the most commonly mutated oncogene in human cancers
(around 30% of cancers).
Mutations in RAS usually affect which region ?
The region which is response for GTPase activity
Explain for me what will happen if the region of GTPase activity is mutated?
GTP—❌—> GDP
causing it to be continuously
activated and leading the cell to
continuously proliferate. ( cancer)
Which protein is responsible for stimulation of the GTPase activity of RAS to prevent its continuous activity?
GTPase-Activating Proteins
When there is a mutation in GTPase-Activating Proteins what will happen to
1- Loss of GTPase activity,
2- GTP—❌—> GDP
3- resulting in continuous activation of RAS and continuous signalling for cell proliferation.
An example of a GAP (GTPase-Activating Protein) is :
Neurofibromin (NF-1)
What is the type of Neurofibromin (NF-1) of gene cancer ?
tumor suppressor gene
Transcription factors are………. present in the…… and are
responsible for…….. of genes that drive cell…..
proteins
nucleus
transcription
growth
What is the example of Nuclear Transcription Factors ?
MYC
Transcription يعني نسخ
كأني اقول انسخ ماي سيدي
Binding of which two proteins to leads to progression of the cell cycle ?
cyclin and a CDK
…………. silence CDKs and inhibit progression of cell cycle.
CDK inhibitors (CDKI)
In the Cyclins & Cyclin-Dependent Kinases (CDKs) mutation what happen?
gain-of function mutations or loss-of function mutations
gain
In the CDK inhibitors (CDKI) mutation what happen?
gain-of function mutations or loss-of function mutations
Loss
.……………are the most commonly mutated genes in this
group and occur in many types of cancers. These are responsible for
the G1/S checkpoint
Cyclin D and CDK4
What is the commonly mutated genes in the Cyclins & Cyclin-Dependent Kinases (CDKs)?
Cyclin D and CDK4
Also, loss-of function mutations in CDKI is a common occurrence in
many cancers Examples include……….
CDKN2A (p16) loss
…….occurs in many tumors such as pancreatic cancer
CDKN2A ( p16)
Genes considered dominant ?
Oncogenes
because mutation of one allele is sufficient to produce the oncogenic effect.
genes that normally prevent uncontrolled growth.
Tumor Suppressor Genes (TSGs)
Genes that considered recessive……..
Tumor Suppressor Genes (TSGs)
Genes that protect against apoptosis are often overexpressed in……..cells.
cancer
• Point mutations that convert proto-oncogenes to oncogenes are
activating/ inactiving mutations. (Example: genes)
Activaing
RAS
Point mutations in tumor suppressor genes………..or……. the function
of the protein products, and are therefore activating/inactivating mutations.
(Example: TP53 gene)
reduce or disable
inactivating
Gene Rearrangements include two mechanisms :
- Overexpression of proto-oncogenes
- Creation of novel fusion proteins
Gene Rearrangements include two mechanisms :
- Overexpression of proto-oncogenes
- Creation of novel fusion proteins
Gene Rearrangements include two mechanisms :
- Overexpression of proto-oncogenes
- Creation of novel fusion proteins
cancer gene is present at the.…….site, in the Gene Rearrangements
breakpoint
MYC gene (chromosome 8) is proto-oncogene or in tumor suppressor
proto-oncogene
RAS is proto-oncogene or in tumor suppressor
proto-oncogene
TP53 gene is proto-oncogene or in tumor suppressor
tumor suppressor
Amplification leads to……… of the protein product of a gene.
• In cancer, this mainly affects proto-oncogenes and converts them into……..
overexpression
oncogenes
Amplification leads to……… of the protein product of a gene.
• In cancer, this mainly affects proto-oncogenes and converts them into……..
overexpression
oncogenes
is a state of number of chromosomes that is multiple of the
haploid state (23 chromosome in humans)
Euploidy
Epigenetic Modifications and cancer include.……
These include DNA methylation and histone modification.
The full name of PDGF (Growth Factor) is
platelet derived growth factor
1-…………These are responsible for the G1/S checkpoint
2-…………protein is to regulate the G1/S checkpoint of the cell cycle
1-Cyclin D and CDK4
2-RB
Loss of chromosome 17 results in loss of TP53 gene, an important
tumor suppressor gene is which lesion:
- Gene Mutations (Point mutations)
- Gene Rearrangements
- Gene Deletions
- Gene Amplification
- Aneuploidy
- Lesions affecting MicroRNA
5
What are the pathways of apoptosis?
- Intrinsic
- Extrinsic
…………….. is a mechanism whereby the cells activate enzymes that degrade its own DNA and cellular content, followed by cell fragmentation into small apoptotic bodies.
Apoptosis
……….. : external factors (outside the cell) initiating apoptosis
Examples : …………….
1- Extrinsic pathway of apoptosis
Example through death receptors
………. internal stressors initiate apoptosis
example : ……………………………………………….
Intrinsic pathway of apoptosis
such as DNA damage or loss of growth factors
In normal condition, when we have cell damage and we want the cell to undergo apoptosis:
1. pro- apoptotic proteins are ……..
2. Anti- apoptotic proteins are …….
activated
inactivated
In cancer What happen for genes in the Apoptosis?
In cancerous cell, they don’t want for a damaged cell to die, in order for this cell to survive:
1. pro- apoptotic proteins are …………
2. Anti- apoptotic proteins are ………….
inactivated
activated
What are the categories of regulatory proteins of apoptosis ?
- Pro-apoptotic proteins
- Anti-apoptotic proteins
How to cancer cells evade apoptosis?
This happens through (acquired mutations) that (disable key components) of the intrinsic pathway of apoptosis.
Example of Pro-apoptotic proteins? باااااااااا
- BAX
- BAK
كأنهم متحمسييييين للأكل باااااااااكل (Ba)
Example of Anti-apoptotic proteins ?
Bcl2
هذا عطاء وياها صريحة قال بكل٢ وهو أصلًا ضد التدمير و الاكل
Examples of key molecules that control the intrinsic pathway of apoptosis include……….
BCL2
BAK
Bad
- P53 can also initiate apoptosis,how ?
By activation of BAX and BAK
- If P53 is mutated it can not initiate apoptosis
Or when the DNA repair is failed
MDM2 is an inhibitor of……..
p53
MDM2 [amplification] leads to loss of P53 function
ابغاش تركزي على Amplification
Examples of mechanisms of Evasion of Apoptosis ?
1-MDM2 amplification (MDM2 is an inhibitor of p53).
2- Loss of p53 function (p53 triggers apoptosis in case of failed DNA repair).
3- Overexpression of BCL2, such as in follicular lymphoma through t(14:18)
The release of cytochrome C triggers………
apoptosis
Which of these proteins increase mitochondrial membrane permeability ?
1-BAX
2-BAK
3- Bcl2
1 + 2
increase mitochondrial membrane permeability lead to ……..
cytochrome c leaves the mitochondria
Overexpression of BCL2 lead to which disease?
follicular lymphoma
………………. is when a cell can not divide any more
Senescence
Senescence occurs because of progressive shortening of………… with each cell division.
telomeres
……………….are sequences of DNA present at the ends of chromosomes that protect the chromosomes from degradation
Telomeres
How do cancer cells avoid senescence & acquire limitless replicative capacity?
activation of an enzyme known as Telomerase
What is the telomerase function ?
Telomerase prevents shortening of telomeres with successive cell divisions
A tumour cannot enlarge beyond 1 or 2 mm in diameter unless it has the capacity to………….
induce angiogenesis.
In normal case the angiogenesis is controlled through a balance between angiogenesis promoters and inhibitors.
• In tumors, the balance is skewed in favor of what …….? promoters or inhibitors
promoters
How does the tumor acquire the capacity of Sustained Angiogenesis?
This occurs through increased / decreased production of angiogenic factors and
increased / decreased of angiogenic inhibitors,
increased
decreased
One of the most common mechanism is production of pro angiogenetic factor is ……… give me the full name
VEGF (Vascular endothelial growth factor) an
angiogenic factor which is overexpressed in many cancers
commonly in tumors you can find hemorrhage and accumulation of blood inside the tumor (why?)
Tumor blood vessels are not entirely normal, They are leaky and not well-formed
How can we recognise unusual and haphazard appearances of the tumour?
We can recognized the appearances by using (Angiograms).
Angiograms is imaging techniques that target blood vessels
…………are the major causes of cancer-related morbidity and mortality.
Invasion & metastasis
Invasion & Metastasis are result from complex interactions between
1- ……………
2-…………….
3-…………….
1-cancer cells,
2-stromal cells,
3-extracellular matrix (ECM)
The process of Invasion & Metastasis can be subdivided into 2 major phases:
• Invasion of the Extracellular matrix.
• Vascular dissemination and homing of tumor cells to distant sites.
- Tumor cells are the parenchyma/stroma
- Surrounding tissues are the parenchyma/stroma
parenchyma
stroma
There are 2 types of extracellular matrix:.
1-
2-
1-Basement membranes of epithelia
2- interstitial connective tissue
In their normal state, the majority of cancer genes have functions related to………,,……….., and…………
cell growth
cell division
cell survival
Types of Cancer Genes
- Oncogenes
- Tumor suppressor genes
- Genes that regulate apoptosis
- Genes that regulate interaction between tumor cells and host cells
An additional class is: DNA repair genes
Examples of Point Mutations :
1-Point mutations that convert proto-oncogenes to oncogenes are
activating mutations. (Example: RAS genes)
2• Point mutations in tumor suppressor genes reduce or disable the
function of the protein products, and are therefore inactivating
mutations. (Example: TP53 gene)
Examples of Point Mutations :
1-Point mutations that convert proto-oncogenes to oncogenes are
activating mutations. (Example: RAS genes)
2• Point mutations in tumor suppressor genes reduce or disable the
function of the protein products, and are therefore inactivating
mutations. (Example: TP53 gene)
Examples of Point Mutations :
1-Point mutations that convert proto-oncogenes to oncogenes are
activating mutations. (Example: RAS genes)
2• Point mutations in tumor suppressor genes reduce or disable the
function of the protein products, and are therefore inactivating
mutations. (Example: TP53 gene)
Gene rearrangements result mainly from chromosomal ……………..
translocations
A new gene is created at the site of the translocation by fusion of two
genes present at the breakpoint sites is …………
Creation of novel fusion proteins
Rearrangements happened between chromosome 9 and 22 resulted in…….. &……… combination (fusion gene), which is a………….
BCR & ABL
tyrosine kinase protein
■ For treatment we give tyrosine kinase inhibitor
In cancer Gene Amplification this mainly affects ………….. genes
(proto-oncogenes) and converts them into oncogenes.
In cancer Gene Amplification this mainly affects ………….. genes
(proto-oncogenes) and converts them into oncogenes.
Two Example of Amplification :
1…….
2……
1- NMYC gene in Neuroblastoma
2- liposarcoma with MDM2 gene amplification.
Example of Growth Factors :
Glioblastoma (A brain tumor) can produce its own growth factor
✨(PDGF) ✨for which it has a receptor.
The majority of growth factor receptors function as…………….
oncoproteins when they are mutated or overexpressed.
Examples of Growth Factor Receptors:
Examples: Epidermal growth factor receptor (EGFR) family members
• ERBB1 (or EGFR) is overexpressed in most carcinomas of the lung and head and neck.
• ERBB2 (or HER2) is overexpressed in 20% of breast cancer, due to gene amplification.
Examples of Growth Factor Receptors:
Examples: Epidermal growth factor receptor (EGFR) family members
• ERBB1 (or EGFR) is overexpressed in most carcinomas of the lung and head and neck.
• ERBB2 (or HER2) is overexpressed in 20% of breast cancer, due to gene amplification.
Examples of Growth Factor Receptors:
Examples: Epidermal growth factor receptor (EGFR) family members
• ERBB1 (or EGFR) is overexpressed in most carcinomas of the lung and head and neck.
• ERBB2 (or HER2) is overexpressed in 20% of breast cancer, due to gene amplification.
An example of GTPase-Activating Proteins is :
is Neurofibromin (NF-1).
………….is mutated in majority of melanomas and in many thyroid cancers.
BRAF
Mutation of BRAF leads to …………..of the signaling pathway
continuous activation
BRAF is a signal transducing protein in the……….
MAP Kinase pathway
Binding of a cyclin to a CDK leads to
Stop / progression of the cell cycle.
progression
