L23 and L24 Genetics of Cancer

Question 1

What origin are most cancer usually manifestations of mutation?

Answer 1

somatic origin

Question 2

what are the 2 ways to be predisposed to cancer?

Answer 2

1. inherited in Mendelian fashion

2. multifactorial causation

Question 3

does the threshold model apply to cancer?

Answer 3

NO

Question 4

define cancer - a disease that progresses by the accumulation of…?

Answer 4

genetic alterations

Question 5

what results from waves of mutation followed by clonal expansion?

Answer 5

tumor progression

Question 6

the property of _______ is unusual among diseases, but is selected for in cancer

Answer 6

progressive aggressiveness

Question 7

on a microscopic scale, what does cancer result from?

Answer 7

Darwinian evolution

Question 8

because cancers tend to occur in 50’s to 60’s, what does this suggest?

Answer 8

that cancer results as a consequence of multiple independent events

Question 9

Give 3 reasons (proof) that cancers CAN be derived from a single, monoclonal cell?

Answer 9

1. x-inactivation in cancer
2. chromosomal abnormality in cancer
3. multiple myelomas produce a monoclonal Ig

Question 10

what acts as switches that regulate cell proliferation and exist at multiple sites along the signal transduction pathway?

Answer 10

proto-oncogenes

Question 11

which ones are the mutant and which ones are normal - proto-oncogenes vs. oncogenes

Answer 11

mutant - oncogenes

normal - proto-oncogenes

Question 12

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

Answer 12

mutant protein

large amounts

Question 13

how is MAP kinase pathway initiated?

Answer 13

by growth factors that interact with receptors

Question 14

what does the activation of MAP kinase pathway trigger? What is the function?

Answer 14

a cascade of activation of kinases => phosphorylation of serine/threonine residues

activates genes involved in driving cell division and amplifies signal through geometric recruitment

Question 15

_____ or _____ can render a receptor constitutively active

Answer 15

truncations or point mutations (or translocations)

Question 16

activation of myc is associated with what cancer?

Answer 16

Burkitt lymphoma

Question 17

activation of alb is associated with what cancer?

Answer 17

Chronic myeloid leukemia (CML)

Question 18

what is the normal function of myc?

Answer 18

transcription factor important for G1/S transition

Question 19

in Burkitt lymphoma, myc expression is under control of IgH promoter, so when IgH increases, what happens to myc?

Answer 19

increases — so you increase stimulation of cell cycle

Question 20

name the powerful tyrosine kinase inhibitor specific for a few tyrosine kinases including abl

Answer 20

imatinib mesylate (formerly STI571)

Question 21

what is the function of Ras?

Answer 21

GTPase involved in the major cell proliferative pathway

Question 22

how is Ras activated?

Answer 22

by binding to GTP

Question 23

what happens when Ras is activated?

Answer 23

it initiates a phosphorylation cascade that activates cellular proliferation

Question 24

how is Ras inactivated?

Answer 24

by intrinsic GTPase activity (GTP–>GDP)

Question 25

Abnormal homogeneously staining regions of chromosomes in cancers often contain _____

Answer 25

amplified oncogenes

Question 26

Name 4 inherited autosomal recessive cancer syndromes of defective DNA repair

Answer 26

1. XP 2. ataxia-telangiectasia 3. Bloom syndrome 4. Fanconi anemia

Question 27

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

Answer 27

WT1 11

Question 28

WRT the Two Hit Hypothesis of TSG, the second hit is usually a ____

Answer 28

loss of heterozygosity (LOH)

Question 29

what is the function of cyclin/Cdk at G1/S phase?

Answer 29

hyperphosphorylates Rb

Question 30

when cyclin/Cdk is present at the G1/S phase, what happens to cells?

Answer 30

they divide! cyclin/Cdk -- hyperphosphorylates Rb -- Rb lets go of E2Fs --- E2Fs activate S-phase genes --- cell divides

Question 31

when there is no cyclin/Cdk around in the G1/S phase, what happens to cells?

Answer 31

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

Question 32

what do virtually all cancer cells show a dysregulation of? what specifically is usually mutated?

Answer 32

the G1/S checkpoint one of the four genes that regulate the phosphorylation of Rb

Question 33

what are the 4 genes that regulate the phosphorylation of Rb?

Answer 33

1. Rb 2. CDK4 3. cyclin D gene 4. CDKN2A (p16)

Question 34

retinoblastoma is due to a mutation of the ____ gene on chromosome ___

Answer 34

Rb 13

Question 35

a loss of Rb gene destroys what? Why?

Answer 35

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)

Question 36

what is a tumor suppressor that control cells life and death?

Answer 36

p53

Question 37

what checkpoint does p53 impinge on?

Answer 37

G1/S

Question 38

what is mutated in more than 50% of all cancers?

Answer 38

p53

Question 39

what does ATR and ATM detect?

Answer 39

DNA double strand breaks

Question 40

who is considered "guardian of the genome"?

Answer 40

p53

Question 41

what are the 3 ways p53 can influence apoptosis?

Answer 41

1. pro-apoptotic Bcl-2 family members 2. Fas receptor (CD 95) 3. IGFBP-3 - sequesters cell survival proteins like IGF1/2 away from receptors

Question 42

what syndrome is a result of an inherited mutation of p53 (TP53)?

Answer 42

Li-Fraumeni syndrome

Question 43

What is the mutation in FAP? what chromosome is the mutation located?

Answer 43

mutation in APC chromosome 5

Question 44

what does APC normally code for?

Answer 44

tumor suppressor

Question 45

APC is a component of the___

Answer 45

WNT signaling pathway

Question 46

when WNT signal is present is there growth or no growth?

Answer 46

growth -destruction complex inactivated -- beta catenin not degraded -- beta catinin moves to nucleus and forms a complex with TCF4 -- activates growth promoting genes

Question 47

when there is NO WNT signal, is there growth or no growth?

Answer 47

no growth -APC interacts with beta catinin --- triggers phosphorylation == uniquination and beta catinin degradation -- low beta catinin levels --- no growth

Question 48

88% of mutations in FAP are found to be disruptions in the _____

Answer 48

APC pathway

Question 49

What type of an event is APC mutation considered?

Answer 49

early gatekeeper event

Question 50

what type of an event is loss of p53 considered?

Answer 50

late event...

Question 51

FAP --- ___ polyps, progress ____

Answer 51

many | slowly

Question 52

HNPCC --- ____ polyps, progress ___

Answer 52

few rapidly

Question 53

what is the other name for HNPCC?

Answer 53

Lynch syndrome

Question 54

what is HNPCC due to a mutation of?

Answer 54

MMR genes in DNA mismatch repair

Question 55

what are the 2 most common genes responsible for HNPCC?

Answer 55

MSH 2 - chromosome 2 - 60% | MLH 1 - chromosome 3 - 35%

Question 56

define mutator genes?

Answer 56

genes or protein that are not directly involved in control of cell division

Question 57

what do the rumors exhibit in HNPCC?

Answer 57

microsatellite instability

Question 58

what is the MOA of Herceptin?

Answer 58

binds to Her2 and prevents binding of EGF to Her2

Question 59

what are the 3 possible direct roles of epigenetics in tumorigenesis?

Answer 59

1. silencing of tumor suppressor loci cause cell overgrowth 2. loss of imprinting causing activation of growth associated genes 3. microRNAs