Upgrade to remove ads
GI: Genetics of GI neoplasms: Gromley
Terms in this set (43)
Continuous cell division and limitless
Can somatic cells divide indefinitely?
No, they have a predetermine number of divisions called their replicative capacity
Process by which a cell irreversibly exits the cell cycle, but remains metabolically active
Cells measure the physiologic stress they experience over extended periods of time and stop proliferating once the damage exceedsa certain threshold
--Free radicals and stuff, yo.
What method does the cell use to measure how many replicative generations it has passed through?
What must a tumor cell find a way to by pass to achieve limitless replicative capacity?
Senescence and telomere length
repeating TTAGGG what is it
From what end is a section of telomere lost during each replication cycle??
5' end of the lagging strand
-due to lack of DNA upstream to ligate to
What can contribute to losing telomere length?
inefficient telomerase activity
as an organism ages the telomeres become progressivly shorter
What is telomerase anyway?
RNA-dependent DNA polymerase
Contains both proteins and RNA template
RNA template has complimentary sequence to repeating sequence in the telomere
~ 90% of human tumors are telomerase positive
What are proto-oncogenes? How are oncogenes different?
Proto-oncogenes are genes that encode proteins that function to receive or transmit cellular growth-promoting signals
They can become oncogenes if they undergo
a mutation that causes them to be
constitutively active (always "on")
Are oncogenes dominant? What about their activity?
Most oncogenes are dominant
Only one allele has to be affected to cause an abnormality
Inappropriate activation or constitutive activation
"Gain of function" mutations
What pathway has the greatest importance to human cancer pathogenesis?
Ras-MAPK, mitogenic pathway
What do 20% of all human tumors contain?
activating Ras mutations
What do 67% of melanomas contain?
activating B-RAF mutations
What do tumor suppressor genes do?
Many tumor suppressor genes encode proteins that control cell cycle progression
Rb, p53, Cdk inhibitors (p21, p16Ink4a)
Are tumor suppressors dominant? What about their activity?
Most tumor suppressors are recessive
Both alleles have to be affected to cause an abnormality
"Loss of function" mutations
"Two hit" model
What is the two hit model?
Mutation event inactivates one allele of a tumor suppressor,
but the unaffected allele can still function
A second mutation event must occur that inactivates the
unaffected allele, resulting in the complete functional
elimination of the tumor suppressor gene
What is the typical source of first hit in tumor suppressor inactivation?
Point mutations in the coding
sequence of a tumor suppressor
gene can result in the production
of a non-functioning protein
What is a common second hit in tumor suppressor inactivation?
Loss of heterozygosity (LOH)
The loss of normal function of one allele of a gene in which the other allele was already inactivated
Is a loss of heterozygosity or point mutations more common?
loss of heterozygosity occurs at a higher frequency
What are some common methods of loss of heterozygosity?
What is a type of gene silencing?
Covalent attachment of a methyl group
to cytosine bases in promoter regions
Only occurs in cytosine bases that are
located 5' to guanosines
Regulates the transcription of associated
Methylation of promoter= gene is
not transcribed (repressed)
De-methylation of promoter= gene
is transcribed (de-repressed)
*In cancer cells, promoter methylation is
another important method for turning
off tumor suppressor genes*
What is induced by an absence of survival signals (growth factors, mitogens) or DNA damage?
these must be bypassed by cancer cells
What are the pro apoptotic members of the Bcl family?
Channel forming (associated with mitochondrial membrane)
What are the anti-apoptotic members of the Bcl family?
When are BH3- only proteins activated?
BH3-only proteins (Bim, Bad, or Bid) are activated in response to cellular stress/apoptotic stimulus
-Bax/Bak are allowed to oligomerize
--Bax/Bak create channels that allow leakage into the cytoplasm (i.e. cytochrome c)
---The caspase cascade is activated
What are the 3 super long ways p53 can evoke an apoptotic response?
Three ways activated p53 can evoke an
1) Induce expression of the gene
encoding the Fas receptor, causing
display of this death receptor at the
cell surface, sensitizing the cell to
any Fas ligand in the extracellular
2) Induce expression of IGF-binding
protein-3 (IGFBP-3), which is
released into the extracellular space,
where it sequesters IGF-1 and IGF-2,
3) Induce expression of Bax, a pro-
apoptotic protein that causes the
release of cytochrome c from the
Cancers due to accumulation of genetic mutations over time in an individual
NOT due to inherited mutation
Sporadic mutations can be passed on to progeny IF mutation occurs in a germ cell
A majority (80%) of cancer cases are sporadic
Cancers that occur in families more often than what would be expected by chance
Due to a combination of risk factors that include inherited susceptibility and
Represents 15-20% of cancer cases
Cancer that results from genetic mutations that are passed on from one generation to
Only 5-10% of cancer cases are due to inheritance
multiple primary cancers
relatives with same type cancer
multiple generations have it
unusual presentation of cancer (male with breast cancer)
weird tumor histology
cancer with birth defects (Wilms)
things that suggest hereditary
Tumor-like growths that increase the risk for colon cancer
Can be sporadic or associated with inherited syndromes
associated with mutations in
LKB1/STK11 is a tumor suppressor
Normal function is to activate the adenine monophosphate-activated protein
kinase (AMPK) in conditions of hypoxia or low energy
AMPK prevents activation of mTOR, causing the cell to stop growing/proliferating
Mutation of LKB1/STK11 *allows the cell to continue to grow in an environment
of low energy resources and hypoxia* (which pre-neoplastic cells commonly
associated with mutations in the TGF-beta/BMP signaling pathway
*BMPR1A (Bone Morphogenetic Protein Receptor)
Receptor for bone morphogenetic protein (BMP)
Component of gene regulatory complexes*
Normally, activation of this pathway causes the repression of the oncogene myc
When the pathway is deactivated by these mutations, unregulated activity of myc occurs,
resulting in persistent growth and proliferation signals
The myc oncoprotein family consists of three
Expressed in most rapidly proliferating
Expressed in pre-B cells, kidney, brain,
Expressed during embryogenesis in the
kidney and lung
Transcription factors with roles in controlling
cell cycle progression, apoptosis, and
Upregulates cyclins, downregulates CDK
Amplification of the ____ gene is common
What mutation is common in both Cowden Syndrome and Bannayan-Ruvalcaba-RIley syndrome?
Loss of function mutations in PTEN
Upon binding of growth factor to its receptor tyrosine kinase (RTK), PI3K
(phosphatidylinositide 3-kinase) becomes activated and phosphorylates PIP2 to produce
PIP3, resulting in the activation of the downstream kinase AKT (PKB), which induces cell
growth and survival
is a phosphatase that acts to reverse this signaling event by de-phosphorylating PIP3,
reverting it back to the PIP2 form, shutting down the signaling cascade
Cowden Syndrome and Bannayan-Ruvalcaba-Riley Syndrome
Familial Adenomatous Polyposis (FAP)
Afflicted individuals acquire hundreds to thousands of polyps by their teenage years
Predisposes individuals to colon cancer
~100% risk of colon cancer if this mutation is inherited
Tumor suppressor gene
Normally inactivates β-catenin
When mutated, APC cannot inhibit β-catenin
Results in overexpression of genes regulated by β-catenin, including myc
Predisposes individuals to colon cancer and endometrial cancer
Characterized by the presence of sessile serrated adenomas in the colon
Associated with mutations in
MLH1 or MSH2
Encodes proteins involved with mismatch repair (DNA damage repair)
Inactivation leads to an increase in point mutations and also genetic instability in
microsatellite regions (regions of simple sequence repeats, such as AAAAAA... or
tandem repeats, such as ATCCTATCCTATCCTATCCT....etc)
Known as the Replication ERror positive (RER+) phenotype
~80% risk of cancer if mutation is inherited
Hereditary Non-polyposis colon cancer
Active during DNA replication when an
incorrect but normal base is incorporated
into the growing chain
The mismatch repair enzyme complex removes
a segment of the newly synthesized DNA that
includes the mismatched bases
DNA polymerase and ligase repair the gap
DNA mismatches are due to replication error
First hit is a mutation in APC, a tumor suppressor gene
Second hit involves the inactivation of other APC allele, along with activation of the oncogene beta-catenin
Then the proto-oncogene K-RAS is converted to its oncogenic form
Late events include p53 mutations (and LOH) as well as mutations in SMAD genes and hyperactivity of telomerase
It can take between 7 and 10 years for a benign adenoma to transform into an adenocarcinoma
Sporadic Colon Cancer (Adenocarcinoma)
THIS SET IS OFTEN IN FOLDERS WITH...
GI: Liver: Yow
GI: tumors of intestines: Wang
GI:Pharm Hep: Weaver
GI: Bowel Disease: Yow
YOU MIGHT ALSO LIKE...
Chapter 16: Cancer Genetics
Tumor Suppressor Genes 1
Unit 6 Genetics
Biology, 2nd semester exam, cancer
OTHER SETS BY THIS CREATOR
Level 3 Truelearn
OBGYN step 3