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Spring Semester > Genetics- Cancer > Flashcards

Genetics- Cancer Flashcards

1
Q

cancer

A

a genetic disease caused by abnormal expression of normal gene products or by gene products expressed from mutant genes. Some mutated genes may be inherited but most are mutated by environmental factors

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2
Q

what causes cancer?

A

caused by a series of genetic changes

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3
Q

Cancer step 1

A

most cancers originate in a single cell- a cancerous growth can be considered to be clonal

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4
Q

cancer step 2

A

at the cellular and genetic levels, cancer is usually a multistep process that begins with a precancerous genetic change ( a benign growth) like a missense mutation affects a protein function. Then, as cell division increases, additional genetic changes occur that cause progression to malignant tumor growth

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5
Q

cancer step 3

A

once a cellular growth has become malignant, the cells are metastatic, they are also invasive

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6
Q

invasive

A

can invade healthy tissue cells

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7
Q

benign vs malignant

A

benign is noncancerous and malignant is cancerous

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8
Q

why don’t all cells become cancer cells?

A

growth factors often stimulate cells in Go to re-eneter the cell cycle by activating cell signaling pathways –there are three checkpoints in cell cycle

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9
Q

what are the go signals for the cell cycle?

A

cyclins and Cdks & they have a cyclic pattern

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10
Q

what stops cells from continually dividing?

A

crossroads at the checkpoint in G1 @ this checkpoint there is a crossroad of proceeding to S phase or withdraw and go to G0

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11
Q

What are the stop signals in the cell cycle?

A

checkpoints– there are three

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12
Q

what are the three checkpoints ?

A

G1/S checkpoint: (most important) cell monitors size and DNA integrity
G2/M checkpoint: cell monitors DNA synthesis and damage
M checkpoint: cell monitors spindle formation and attachment to kinetochores (prevents aneuploidy)

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13
Q

Cell cycle control system is a combination …

A

of positive factors (GO signals) that push cells through the cell cycle and negative regulators (STOP signals, checkpoints)

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14
Q

Cancer is uncontrolled cell division

A

1) activate positive regulators = oncogenes

2) inhibit checkpoint regulators = tumor suppressors

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15
Q

How to turn a proto-oncogene into an oncogene

A

Many proto-oncogenes function in growth factor signaling pathways and oncogenes are their hyper-active versions. Proto-oncogenes are turned into oncogenes by activating them with:

a) missense mutation in the coding sequence
b) gene amplification
c) chromosomal rearrangement that increases expression
d) chromosomal rearrangement that forms a hyperactive fusion protein
e) viral integration

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16
Q

Function of changing proto-oncogene into an oncogene

A

gain of function so only need one allele to be activated into an oncogene to make cell cancerous

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17
Q

Loss of herterozygosity

A

lose the other functional gene so no functional tumor suppressor proteins – inherit one mutant & environment mutates the other –tends to be inherited in a dominant fashion and can result from a point mutation in the normal allele or occurs if chromosome carrying good copy is lost

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18
Q

two-hit model

A

ways to lose the only good copy of a tumor suppressor gene

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19
Q

two-hit model ways

A

a) mitotic non-disjunction (=aneploidy) causes the chromosome with the wild type gene to be lose
b) duplication of chromosome with mutated gene
c) mitotic recombination can lead to two mutant genes
d) gene conversion where WT becomes mutant
e) deletion of the normal gene
f) point mutation in normal gene

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20
Q

Another two hit model

A

any genetic or epigenetic mutations that inhibit expression of the wild type tumor suppressor gene may lead to cancer

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21
Q

p53

A

is a tumor suppressor gene
considered the “guardian of the genome” kills any cells with DNA damage, telomere shortening, hypoxia, and hyper proliferative signals

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22
Q

dominant mutation

A

gain of function, where single mutation event in proto-oncogene creates oncogene by activating mutation enables oncogene to stimulate cell survival and proliferation
-only need one copy

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23
Q

recessive mutation

A

loss of function, BUT inherited in a dominant fashion, where the two mutation event inactivates tumor suppressor gene so the two inactivating mutations functionally eliminate the tumor suppressor gene, stimulating cell survival and proliferation
-need both copies inactivated

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24
Q

cancer is usually…

A

a result of multiple genetic changes

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25
Q

metastasis

A

ability to leave surrounding cells&raquo_space; invade blood vessels» invade a different tissue&raquo_space;grow and proliferate there (=secondary/tertiary tumors)

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26
Q

angiogenesis

A

cancer cells secrete factors that stimulate the growth of blood vessels (to feed growing cancer cells)

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27
Q

COSMIC

A

catalog of somatic mutations in cancer

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28
Q

Hallmarks of cancer

A

a) sustained proliferation of cells
b) evasion of growth suppressors
c) avoid destruction by immune system
d) immortality of cells
e) cause tumor-promoting inflammation
f) activate metastasis
g) angiogenesis
h) genome instability
i) resist cell death
j) deregulate cellular energetics

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29
Q

Treat hallmark of sustained proliferation of cells

A

inhibit mitosis, block growth hormone receptors & inhibit kinases

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30
Q

Treat hallmark of evasion of growth suppressors

A

inhibit cell-cycle promoting proteins

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31
Q

Treat hallmark of avoid destruction by immune system

A

activate immune system (immunoncology)

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32
Q

Treat hallmark of immortality of cells

A

inhibit telomerase

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33
Q

Treat hallmark of cause tumor-promoting inflammation

A

some anti-inflammatories

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34
Q

Treat hallmark of activate metastasis

A

inhibit invasion of other tissues

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35
Q

Treat hallmark of angiogenesis

A

inhibit angiogenesis

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36
Q

Treat hallmark of genome instability

A 
PARP inhibitors (recently successful) 
easier to make drugs that inhibit rather than activate
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37
Q

Treat hallmark of resist cell death

A

pro-apoptotic drugs

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38
Q

Treat hallmark of deregulate cellular energetics

A

aerobic glycolysis inhibitors

39
Q

cancer is a disease characterized by …

A

characterized by uncontrolled cell division
•It is a genetic disease at the cellular level
•More than 100 kinds of human cancers are known
–These are classified according to the type of cell that has become cancerous
not a single disease but a collection of diseases & not really inherited

40
Q

What makes a cell cancerous?

A
  • Growth self-sufficiency
  • Protection from apoptosis (death)
  • Angiogenic Capacity (growing blood vessels to feed itself)
  • Limitless division (biggest hallmark)
  • Invasion and metastasis
41
Q

normal control of cell division

A 
• Cell	cycle	is	HIGHLY	
REGULATED
• Many	CHECKPOINTS	to	
ensure	the	cell	and	its	
DNA are	normal before	
continuing through	
division
• Mutations to	
checkpoint genes	are	
often involved in cancer
42
Q

G2 checkpoint

A

check for cell size & DNA replication

43
Q

Spindle Assemble Checkpoint

A

check for chromosome attachment to spindle

44
Q

G1 checkpoint

A

check for cell size, nutrients, growth factors, DNA damage

45
Q

Cancers arise when critical genes are mutated causing.. .

A 
unregulated proliferation
of cells.
These rapidly dividing
cells pile up on top of each
other to form a tumor
46
Q

once malignant

A

the cells are invasive

47
Q

cells have a great many defects by the time they …

A

become cancerous

48
Q

Cancer cells are clones of the initial cell gone bad

A
  1. a cell is predisposed to proliferate at an abnormally high rate
  2. a second mutation causes the cell to divide rapidly
  3. after a third mutation, the cell undergoes structural changes
  4. a fourth mutation causes the cell to divide uncontrollably and invade other tissues
49
Q

cancer has a clonal origin

A

Cancer results from cells in a single lineage
accumulating enough mutations to outgrow
normal cells.
Most cancers originate in a single cell

50
Q

cancer is a result of multiple mutations

A

• A single mutation usually does not result in cancer
• Usually several genes that regulate cell growth are
mutated before a cancerous state results.

51
Q

tumor

A

a clonal group of cells that arose from a prerecessor

52
Q

inherited predisposition

A

only 5-10% of cancers

BRCA1 or BRCA2 mutations lead to breast cancer

53
Q

spontaneous or induced mutation

A

90-95% of cancers
about 80% are related to exposure to mutagens
about 20% are spontaneous & not a response to something external

54
Q

Model

A

a small # of initial mutations&raquo_space;increased mutation frequency ‘genetic instability’&raquo_space; more mutations&raquo_space;cancer

55
Q

predisposition for developing cancer

A

often the result of being heterozygous for one of these genes

56
Q

types of cancer-causing genes

A

1) tumor suppressor
2) proto-oncogene
3) repair gene

57
Q

tumor suprresor

A

normal function: suppresses cell division when mutated fails to suppress division ( loss of function mutation)
–growth factor inhibitors (type of protein)

58
Q

proto-oncogene

A

normal function is to promote division but when mutated promotes division at abnormal levels or in cells that shouldn’t divide (gain of function mutation)
–growth factors (types of protein)

59
Q

repair genes

A

normal function is to repair DNA mutations but when mutated fail to repair DNA mutations (loss of function)
–enzymes (type of protein)
work with the other two to cause cancer

60
Q

when p53 is on

A

tumor suppressor gene
inhibits cell cycle/excessive proliferation & must lose BOTH copies to lose inhibition
–loss of function
–recessive

61
Q

the two hit hypothesis

A

two mutation in the same tumor suppressor gene are required to initiate cancer

  • sporadic
  • familial
62
Q

sporadic cases

A

the cancer begins with two somatic mutations (in a gene like retinoblastoma, or APC)

63
Q

familial cases

A

the cancer begins with only a single somatic mutation, because the individual has inherited a mutation in a cancer causing gene (predisposes you more)

64
Q

consequence of two hit hypothesis

A

if they get another mutation in the same gene, that cell now has a chance to begin dividing out of control, and accumulating more mutations. Eventually this can lead to cancer

65
Q

tumors suppressor gene can appear to be dominant at the organismal level BUT

A

at the cellular level be recessive

66
Q

proto-oncogenes act dominantly at the cellular level

A

Genes that promote cell division when mutated, become
“oncogenes”
• Cancerous situations:
• Expression of oncogene at the wrong time or in the wrong cell type
• Mutation (dominant) causes
protein to be always “ON”= GAIN OF FUNCTION MUTATION!

67
Q

tranformation

A

the process of converting a normal cell into a malignant (cancerous) cell

68
Q

Oncogenes were found because of their

ability to “transform” cells

A 
Rous	Sarcoma	virus,	sarcoma	in	chickens
needs	a	vial	oncogene,	“
v-src
” (viral	sarcoma)
Nobel	1966	for	Rous	(virus	discovery)
Bishop	and	Varmus	found	a	cellular	version	called	c–src (for	cellular	
src)	 Nobel	1989
c-src is	incorporated	into	viral	genome	during	infection	and	becomes	
v-src
69
Q

the most famous oncogene

A

activated RAS
oncogenic RAS is active even if no EGF present
when Ras is active we get cell division & mutation prevents RAS from being regulated always active

70
Q

Chromosomal rearrangements can result in cancer

A

A chromosomal translocation turns abl into an oncogene
-normal order of gene is disrupted
The chromosomal rearrangement changes when and where the abl gene is expressed: abl now active all the time, in white blood cells

71
Q

strategies for battling cancer

A
  1. surgical intervention (confined tumor)
  2. radiotherapy (targeted radiation)
  3. chemotherapy (most used-only one generally useful for invaded or metastatic cancers)
  4. immunotherapy (new and shows a lot of promise)
72
Q

immunotherapy

A

generating T cells that specifically target cancer cell–will not work in immune-compromised patients

73
Q

why genetics makes treatment so hard

A

Hallmarks of cancer: predictable phenotypes in the progression of cancer

  • clonal origin so mutation A occurs randomly in a single cell & expansion creates local population of A’ cells
  • Polyclonal tumor
74
Q

polyclonal tumor

A

layers of mutation/expansion

75
Q

treating a tumor like an infection

A 
Successful	treatment	requires	separation
of	tumor	 from	host	cells
Less	similar	 cells	are	easier	 to	target
More	“druggable targets”
- Specific	 to	infection
- Consistent	 within	infection
76
Q

Bacterial infection

A 
Infecting	cells	are	very	
different	from	host
Side-effects	of	antibiotics
few,	except	 for	misuse	 and	
development	 of	resistance
77
Q

Fungal infection

A

Both host and infection are
eukaryotic cells
Side-effects of antifungals
More common, varying

78
Q

cancer infection

A 
Host	and	infection	are	
same	species	 and	same	
individual
Side-effects	of	anticancer	
therapy
Extremely	 common	and	
severe!
79
Q

Chemotherapies DNA as a target

A

Most cancer cells use their DNA more than most normal cells
Fast division = high levels of flux
through DNA pathway

80
Q

Doxorubicin drug

A

fragment the DNA

81
Q

Cisplatin drug

A

glue the strands together

82
Q

Methotrexate drug

A

attack the supply chain

83
Q

Taxol drug

A

prevent separation of replicated DNA

84
Q

traditional chemotherapy

A

targets production and common manipulations of DNA

85
Q

Side effects of Chemotherapy on any replenishing (stem) cell

A 
Bone	marrow,	skin,	hair,	intestine,	 germ	
line
All	these	 cells	 look	like	cancer	cells	in	
terms	of	DNA	use
The	drugs	are	doing	EXACTLY what	they	
are	supposed	to	do!
DNA	use	is	inadequate	 for	specific	
targeting	 to	cancer
86
Q

Side effects of Chemotherapy on some other cell type

A

Drug-specific interactions cause toxicity
in some other tissue
Often unpredictable for new drugs
Unique for each drug or class of drugs
Cardiac toxicity, deafness, liver toxicity,
neuropathy

87
Q

Chemotherapy success

A

moderately successful strategy
different tissues, different results in overall survival and in stage-specific survival
we are great at breast cancer but not good in pancreatic

88
Q

why difference in success?

A

accessibility to cancerous cells
localized
regional invasion

89
Q

Rational drug design

A

target something that is unique about cancer cell
use genetics of the tumor to direct the treatment
-Targeted therapy
-Prodrug therapy

90
Q

Leukemia (CML)

A

Gleevec treats it and has a high survival rate

91
Q

other possible cancer treatment approaches

A

• Block receptors for growth factors that make cells divide
–angiogenesis
–Her-2/neu breast cancer (cells have extra growth factor receptors):
drug Herceptin
• Engineer viruses that can only replicate or infect cancer cells;
when the viruses replicate they will kill the cancer cells

92
Q

molecular profiling to classify tumors

A 
identifying the genes	
involved	in making a	cancerous cell.
• Use	microarrays	to	identify	up regulation
or	down-regulation
• Look	for	correlations	between	
genes	that	are	mis-regulated
• Sequencing	cancer	cells!
93
Q

cancer genome challenge

A

individual scientists from all over sequencing as many cancers as possible (profiling)

Spring Semester (13 decks)

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