Genetics of Cancer: Oncogenes and Tumor Suppressors Flashcards
types of genetic diseases (4)
chromosome disorders
single gene disorders
multifactorial or complex
sex linked and mitochondrial
chromosome disorders (4)
rearrangements/translocations
deletions
insertions
duplications
single gene disorders (3)
dominant
recessive
codominant
multifactorial or complex (2)
multiple genes
gene environment
Chronic Myelogenous Leukemia (CML)
Bone marrow produces excessive amounts of abnormal granulocytes at the expense of the other healthy white blood cells
The Philadelphia chromosome, creates a fusion of the (2) genes
BCR and ABL
BCR
break point cluster region
BCR + ABL =
oncogene
what lineages can the blood stem cell differentiate into?
myeloid
lymphoid
is a single mutation enough to cause cancer?
no
while cancer predisposing mutations can be (and often are) —, cancer or tumor formation is a — — involving other mutations and environmental factors
inherited
somatic event
most inherited mutations associated with cancer affect a persons
risk for developing cancer
can caner be inherited?
no, it is somatic. it can increase your risk of developing cancer, but that doesn’t mean you will get it because it takes multiple things to accumulate
tumor growth and progression generally involves
multiple, successive rounds of genetic changes with the end results of natural selection of a clonal cel that produces a tumor or cancer
rumors can arise from (2)
increased cel division
decreased apoptosis
normal cell division and normal apoptosis leads to
homeostasis
increase cell division and normal apoptosis leads to
tumor
normal cell division and decreased apoptosis leads to
tumor
tumors can arise from (2) changes
genetic
epigenetic
penetrance
how many people that inherit a genetic change experience the phenotype
we carry different variants of genes, with different
penetrance
higher relative risk associated with rare, high-penetrance genetic variants, such as mutations in the — genes associated with hereditary breast and ovarian cancer and the mismatch repair genes associated with Lynch syndrome
BRCA1/ BRCA2
how are malignant tumors classified
according to the tissue or cell type from which they originated
carcinomas
cancers arising from epithelial cells
sarcomas
arise from connective tissue or muscle cells
leukemias
derive from WBC and their precursors (hematopoietic cells)
gliomas
derive from glial cells of the CNS
benign tumors are
likewise classified
adenomas
benign epithelial tumors with glandular organization
chondromas
arise from cartilage
benign tumor
tumor contained within tissue they originated in
malignant tumor
tumor moves out of tissue it originated in to invade/metastasize
risk factors for cancer (5)
occupational exposure
tobacco related
diet (low in vegetables, high salt, high nitrate)
diet (high fat, low fiber, fried and broiled foods
tobacco and alcohol
top 2 % of total cases
tobacco related (24) diet (high fat, low fiber, fried and broiled foods) (37)
many cancers are maintained by a population of
cancer stem cells
cancer stem cells generally divide
more slowly
cancer stem cells may survive
radiate and or chemotherapy as these treatments generally target more rapidly dividing cells
tumors secrete — signals
angiogenic
tumor angiogenic signals promote the formation of new
blood vessels need to supply the nutrient needs of the growing tumor
these new blood vessels also provide a means by which — can colonize distant sites
metastasis
cancer cells are more — — than normal cells
self sufficient
cancer cells are relatively insensitive to
anti-proliferative extracellular signals
cancer cells are less prone to undergo
apoptosis
cancer cells are defective in the control mechanisms that normally
halt cell division
cancer cells induce help from normal — cells in their microenvironment
stromal
cancer cells induce
angiogenesis
cancer cells can survive and proliferate in
foreign sites
cancer cells are genetically
unstable
cancer cells produce — or acquire another means of …
telomerase
stabilizing their telomeres
classification of cancer genes (3)
genes that normally inhibit cellular proliferation
genes that activate proliferation
genes that participate in DNA repair
Oncogenes
mutated forms of certain normal genes of the cell called proto-oncogenes
Proto-oncogenes are often genes that normally control
what kind of cell it is and how often it grows and divides
When a proto-oncogene mutates (changes) into an oncogene, it
turns on or activates when it is not supposed to be
When this occurs, the cell can grow out of control, leading to —
cancer
Tumor suppressor genes are normal genes that (3)
slow down cell division
repair DNA mistakes
tell cells when to die (apoptosis or programmed cell death)
When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to —
cancer
An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the — of proto-oncogenes, but tumor suppressor genes cause cancer when they
are —
activation (turning on)
inactivated (turned off)
RB1
Rb protein binds to E2F to brake cell cycle
p16
CDK inhibitor
p53
inhibits cell cycle arrest or apoptosis
APC
intracellular component of degradation complex of beta-catenin signaling pathway
BRCA1 interacts with — repair protein
RAD51
BRCA2 interacts with — repair protein
RAD51
what did Alfred Knutson invent
2 hit hypothesis of Rb
Knudson’s original hypothesis was that
a person needed to acquire two mutant copies of the Rb gene
This could be accomplished by a (2)
germline mutations inherited from one parent (carrier) and then a somatic second mutation/event in the normal allele
The Rb protein is a “universal” cell cycle —
regulator
Normal Rb protein functions as a
brake on cell cycle progression
One mutant Rb allele is considered — at the level of the individual, but — at the level of the cell
dominant
recessive
other considerations (4)
type
hormone receptor status
ki-67 proliferation index
her2/neu status
The somewhat paradoxical contradiction can be explained by realizing that
only a single tumor cell is required to produce a tumor, and in any individual who has inherited a mutant Rb allele it takes only a second hit in one cell to create a tumor
Thus it is the strong predisposition to develop a tumor that is inherited as a — trait
dominant
The Rb mutation also displays reduced —, only about –% of individuals who inherit the mutant allele experience a second hit and develop a tumor
penetrance
90
The p16 protein (product of the INK4 gene) is produced when cells are — and is an
important component of the cell cycle — that should normally occur
stressed
arrest
Mutations that inactivate the function of p16 or mutations in regulatory regions of the p16 gene that
— — can also contribute to cancer
shutdown expression
one of the most common mutations in cancer
p53
what can lead to activation of p53 (4)
hyper proliferative signals
DNA damage
telomere shortening
hypoxia
types of breast cancer (2)
invasive
noninvasive
noninvasive (2)
- ductal carcinoma in situ (25% of all B.C)
* lobular carcinoma in situ
invasive (3)
Usually epithelial
• Ductal (65-85% of Invasive)
• Lobular (5-10% of invasive)
• Other (10% of invasive)
hormone receptor status (2)
- ER + or –
* PR + or –
-
wont respond
+
drugs to treat tumors are more effective
increased risk genes of breast cancer (3)
BRCA1 (breast cancer 1, early onset)
BRCA2 (breast cancer 2, early onset)
TP53 (p53)
BRCA1/2 pedigree
autosomal dominant syndrome
APC mutations give rise to
colon cancer
release of beta Catelin from degradation complex, goes to the nucleus, cell growth stimulation
high % of colon cancers have mutations in (2)
APC
p53
Unlike the genomes of all eukaryotic and prokaryotic cells, virus genomes can be found
either in the form of (2)
DNA or RNA
Virus genomes can be (2)
single-stranded or double-stranded
linear or circular
~15% of human cancers world-wide are thought to arise from mechanisms that
involve (3)
viruses, bacteria or parasites
two types of viruses
RNA viruses (RNA genome, retrovirus) DNA viruses (DNA genome)
first viral oncogene identified
from the avian rout sarcoma virus (RSV)
oncogene=
cancer genes
most oncogenes have normal cellular homologs called
porto-oncogenes
protconcogenes function as
regulators of cell growth
protooncogenes include (4)
growth factors
growth factor receptors
signal transduction molecules
transcription factors
DNA virus examples (4)
HPV
hep B
hep C
herpesvirus family (Epstein Barr virus)
RNA virus examples (2)
human T cell leukemia virus type 1
human immunodeficiency virus
HIV infects (3)
CD+ T-cells, macrophages and microglial cells
Virus particle consists of 2 identical copies of the
HIV positive single-
stranded RNA genome
The RNA genome is bound to several proteins including key enzymes such as — —, which is needed to create a DNA copy of the HIV genome. Others include (3)
reverse transcriptase
proteases, ribonucleases and integrase
The HIV genome consists of – structural landmarks (regions) and
generally – genes that encode – proteins
7
9 (sometimes 10)
19
Upon entry into the cell, the reverse transcriptase copies the RNA genome into a — and eventually into a — that enters the nucleus and integrates into the host cell genome
ss-cDNA
ds-cDNA
Because reverse transcriptase has a high error rate this results in a
high frequency of mutations in the cDNA copies
influenza virus
8 segments of negative single-stranded RNA that exist in a complex
with various nucleoproteins.
The 8 RNA strands code for – proteins
11
The negative sense RNA is transcribed into a positive sense RNA (cRNA), which serves as a template for (2)
protein synthesis and for negative strands that are incorporated into new viral particles
Influenza virus does not use a DNA copy and as RNA is much less stable than DNA and as such — at a faster rate than any other kind of virus
mutates
