L23 and L24 Genetics of Cancer Flashcards
What origin are most cancer usually manifestations of mutation?
somatic origin
what are the 2 ways to be predisposed to cancer?
- inherited in Mendelian fashion
2. multifactorial causation
does the threshold model apply to cancer?
NO
define cancer - a disease that progresses by the accumulation of…?
genetic alterations
what results from waves of mutation followed by clonal expansion?
tumor progression
the property of _______ is unusual among diseases, but is selected for in cancer
progressive aggressiveness
on a microscopic scale, what does cancer result from?
Darwinian evolution
because cancers tend to occur in 50’s to 60’s, what does this suggest?
that cancer results as a consequence of multiple independent events
Give 3 reasons (proof) that cancers CAN be derived from a single, monoclonal cell?
- x-inactivation in cancer
- chromosomal abnormality in cancer
- multiple myelomas produce a monoclonal Ig
what acts as switches that regulate cell proliferation and exist at multiple sites along the signal transduction pathway?
proto-oncogenes
which ones are the mutant and which ones are normal - proto-oncogenes vs. oncogenes
mutant - oncogenes
normal - proto-oncogenes
mutation of a proto-oncogene results in the production of a _______ that stimulate cell division and may also involve increase expression of the gene results in production of ____ of a protein that stimulates cell division
mutant protein
large amounts
how is MAP kinase pathway initiated?
by growth factors that interact with receptors
what does the activation of MAP kinase pathway trigger? What is the function?
a cascade of activation of kinases => phosphorylation of serine/threonine residues
activates genes involved in driving cell division and amplifies signal through geometric recruitment
_____ or _____ can render a receptor constitutively active
truncations or point mutations (or translocations)
activation of myc is associated with what cancer?
Burkitt lymphoma
activation of alb is associated with what cancer?
Chronic myeloid leukemia (CML)
what is the normal function of myc?
transcription factor important for G1/S transition
in Burkitt lymphoma, myc expression is under control of IgH promoter, so when IgH increases, what happens to myc?
increases — so you increase stimulation of cell cycle
name the powerful tyrosine kinase inhibitor specific for a few tyrosine kinases including abl
imatinib mesylate (formerly STI571)
what is the function of Ras?
GTPase involved in the major cell proliferative pathway
how is Ras activated?
by binding to GTP
what happens when Ras is activated?
it initiates a phosphorylation cascade that activates cellular proliferation
how is Ras inactivated?
by intrinsic GTPase activity (GTP–>GDP)
Abnormal homogeneously staining regions of chromosomes in cancers often contain _____
amplified oncogenes
Name 4 inherited autosomal recessive cancer syndromes of defective DNA repair
- XP
- ataxia-telangiectasia
- Bloom syndrome
- Fanconi anemia
Wilms tumor results from loss-of-function in the _____ gene on chromosome ____ which encodes a transcription factor important in the control of cell growth and differentiation
WT1
11
WRT the Two Hit Hypothesis of TSG, the second hit is usually a ____
loss of heterozygosity (LOH)
what is the function of cyclin/Cdk at G1/S phase?
hyperphosphorylates Rb
when cyclin/Cdk is present at the G1/S phase, what happens to cells?
they divide!
cyclin/Cdk – hyperphosphorylates Rb – Rb lets go of E2Fs — E2Fs activate S-phase genes — cell divides
when there is no cyclin/Cdk around in the G1/S phase, what happens to cells?
they DONT divide - transcription block
no cyclin/Cdk — HYPOphosphorylated Rb — Rb holds onto E2F complex — now it binds DNA + histone methylase + histone deacetylase –> transcription block
what do virtually all cancer cells show a dysregulation of? what specifically is usually mutated?
the G1/S checkpoint
one of the four genes that regulate the phosphorylation of Rb
what are the 4 genes that regulate the phosphorylation of Rb?
- Rb
- CDK4
- cyclin D gene
- CDKN2A (p16)
retinoblastoma is due to a mutation of the ____ gene on chromosome ___
Rb
13
a loss of Rb gene destroys what? Why?
the G1/S checkpoint
loss of Rb gene does NOT bind to E2F so you get increased transcription of S phase genes (unregulated cell division = cancer)
what is a tumor suppressor that control cells life and death?
p53
what checkpoint does p53 impinge on?
G1/S
what is mutated in more than 50% of all cancers?
p53
what does ATR and ATM detect?
DNA double strand breaks
who is considered “guardian of the genome”?
p53
what are the 3 ways p53 can influence apoptosis?
- pro-apoptotic Bcl-2 family members
- Fas receptor (CD 95)
- IGFBP-3 - sequesters cell survival proteins like IGF1/2 away from receptors
what syndrome is a result of an inherited mutation of p53 (TP53)?
Li-Fraumeni syndrome
What is the mutation in FAP? what chromosome is the mutation located?
mutation in APC
chromosome 5
what does APC normally code for?
tumor suppressor
APC is a component of the___
WNT signaling pathway
when WNT signal is present is there growth or no growth?
growth
-destruction complex inactivated – beta catenin not degraded – beta catinin moves to nucleus and forms a complex with TCF4 – activates growth promoting genes
when there is NO WNT signal, is there growth or no growth?
no growth
-APC interacts with beta catinin — triggers phosphorylation == uniquination and beta catinin degradation – low beta catinin levels — no growth
88% of mutations in FAP are found to be disruptions in the _____
APC pathway
What type of an event is APC mutation considered?
early gatekeeper event
what type of an event is loss of p53 considered?
late event…
FAP — ___ polyps, progress ____
many
slowly
HNPCC — ____ polyps, progress ___
few
rapidly
what is the other name for HNPCC?
Lynch syndrome
what is HNPCC due to a mutation of?
MMR genes in DNA mismatch repair
what are the 2 most common genes responsible for HNPCC?
MSH 2 - chromosome 2 - 60%
MLH 1 - chromosome 3 - 35%
define mutator genes?
genes or protein that are not directly involved in control of cell division
what do the rumors exhibit in HNPCC?
microsatellite instability
what is the MOA of Herceptin?
binds to Her2 and prevents binding of EGF to Her2
what are the 3 possible direct roles of epigenetics in tumorigenesis?
- silencing of tumor suppressor loci cause cell overgrowth
- loss of imprinting causing activation of growth associated genes
- microRNAs
