B2.032 Cancer Mechanisms

Question 1

what proportion of all genes have the potential to cause cancer when mutated?

Answer 1

small

Question 2

are most mutations of cancers somatic or constitutional?

Answer 2

somatic (found only in neoplastic cells)

Question 3

why are constitutional mutations important?

Answer 3

they can predispose to cancer

can be inherited

Question 4

where are the two DNA damage checkpoints in the cell cycle?

Answer 4

1 : before S phase chromosomal duplication

2: before mitosis begins

Question 5

what happens if a normal cell finds DNA damage during the checkpoints of the cell cycle?

Answer 5

most errors are fixed

if there are too many error, cells are left to senescence or die via apoptosis

Question 6

what are some types of chromosomal changes that can lead to dysregulation of cancer-associated genes?

Answer 6

translocations
deletions
gene amplification
chromothrypsis

Question 7

what effects can translocations have?

Answer 7

dysregulation of gene expression (a gene that is usually on could be turned off or vice versa if translocated into a different chromosome)
structural alteration of a gene (weird combo proteins result)

Question 8

what is chromothrypsis?

Answer 8

extensive chromosomal breaks and rearrangements

worst type of chromosomal changes

Question 9

what other changes can affect dysregulation of cancer associated genes?

Answer 9

point mutations
epigenetic changes
noncoding RNAs

Question 10

how can point mutations have a large effect?

Answer 10

can interfere w a critical amino acid
can place a stop codon
in RAS, there is a lack of an inhibitor binding site so the protein can’t be silences

Question 11

what is intraclonal heterogeneity?

Answer 11

not all clonal cancer cells are alike, there is accumulation of new mutations as clonal cells proliferate
allow neoplastic cells to escape and migrate to different sites

Question 12

do all cancers have all of the “hallmarks of cancer”?

Answer 12

yes, not all to the same degree, but all must be present to achieve metastasis and invasion

Question 13

what are the hallmarks of cancer?

Answer 13

avoiding immune destruction
evading growth suppressors
enabling replicative immortality
tumor promoting inflammation
activating invasion and metastasis
genomic instability
inducing angiogenesis
resisting cell death
deregulating cellular energetics
sustaining proliferative signaling

Question 14

what are oncogenes?

Answer 14

genes that promote autonomous cell growth

Question 15

how many copies of an oncogene need to be affected to show an effect?

Answer 15

1, heterogeneous

Question 16

characterize the gain of function possibilities in an oncogene

Answer 16

change in structure can create an abnormal gene product with aberrant function
change in regulation of gene expression can lead to aberrant expression of inappropriate production of structurally normal protein

Question 17

what are the major classes of oncogenes?

Answer 17

growth factors
growth factor receptors
proteins involved in signal transduction
nuclear regulatory proteins
cell cycle regulators

Question 18

what are tumor suppressor genes?

Answer 18

gatekeeper genes, put brakes on cell division

Question 19

how many alleles of a tumor suppressor gene need to be mutated to be inactivated?

Answer 19

2

Question 20

if both alleles are not mutated, how else can you evade tumor suppressor genes?

Answer 20

inactivate protein function

Question 21

which virus is associated with inactivation of protein product of tumor suppressor genes?

Answer 21

HPV

Question 22

how does inheritance factor into the inactivation of tumor suppressor genes?

Answer 22

you need both copies to be mutated
if you inherit a mutation, at least one copy is present in all of your cells
this makes it more likely (100%) for a second mutation to occur, so you would have an early onset form of the disease

Question 23

what is the result of evasion of apoptosis?

Answer 23

allows defected cells to live with excessive DNA damage, therefore this damage persists over time

Question 24

what is a mechanism of apoptosis evasion?

Answer 24

BCL-2 overexpression, protects from mitochondrial apoptotic pathway

Question 25

what genes mediate senescence?

Answer 25

p53 and p16

Question 26

which checkpoint is escaped in the evasion of senescence?

Answer 26

G1/S checkpoint

Question 27

what leads to mitotic crisis?

Answer 27

loss of telomeres as DNA is replicated accumulates over time
sensed as DNA damage
leads to inability to divide (mitotic crisis)

Question 28

how is mitotic crisis escaped?

Answer 28

reactivation of telomerase

Question 29

how is self renewal mediated in cancers?

Answer 29

cancer stem cells are present in every tumor

Question 30

what is tumor angiogenesis?

Answer 30

circulatory system forming within a tumor

Question 31

why is tumor angiogenesis important?

Answer 31

required for growth beyond 1-2mm for any tumor (angiogenic switch)
can be targeted with drugs to stabilize tumor size (but doesn’t kill them)

Question 32

what is the angiogenic switch?

Answer 32

altered balance between angiogenic growth factors (VEGF, FGF, others) and inhibitors

Question 33

what times of enzymes are produced by a cancer cell to break through the basement membrane?

Answer 33

collagenase, elastase, metalloprotease

Question 34

describe the process of a primary tumor metastasizing

Answer 34

1. clonal expansion, growth, diversification, angiogenesis
2. metastatic subclone
3. adhesion to and invasion of basement membrane
4. passage through extracellular matrix
5. intravasation
6. interaction with host lymphoid cells
7. tumor cell embolus
8. extravasation
9. metastatic deposit
10. angiogenesis/growth

Question 35

what is the Warburg effect?

Answer 35

shifting balance towards aerobic glycolysis from oxidative phosphorylation

Question 36

what are the effects of a shift toward aerobic glycolysis?

Answer 36

decreased ATP output
increased glucose uptake
provides metabolic intermediates for synthesis of cellular components (carbon moieties, “building materials”)

Question 37

which mutated genes are utilized in metabolic reprogramming?

Answer 37

P13K/AKT

MYC

Question 38

what are tumor antigens?

Answer 38

products of mutated genes
overexpressed or aberrantly expressed cellular proteins
cell type-specific differentiating antigens

Question 39

what are some antitumor effector mechanisms?

Answer 39

cytotoxic T lymphocytes
natural killer cells
macrophages

Question 40

how can a tumor cell escape immune response?

Answer 40

selective outgrowth of antigen-negative variants
loss or reduced expression of MHC molecules
activation of immunoregulatory pathways
secretion of immunosuppressive factors by cancer cells
induction of regulatory T cells

Question 41

what are some sources of genomic instability that can lead to cancer?

Answer 41

defective mismatch repair genes
defective nucleotide excision repair
defective DNA repair by homologous recombination

Question 42

what are the steps of inflammatory reaction to infiltrating cancer?

Answer 42

release of growth factors that promote proliferation
removal of growth suppressors
enhanced resistance to cell death
inducing angiogenesis
activating and assisting invasion and metastasis
evading immune destruction