Genetics- Cancer Flashcards Preview

Spring Semester > Genetics- Cancer > Flashcards

Flashcards in Genetics- Cancer Deck (93):
1

cancer

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

2

what causes cancer?

caused by a series of genetic changes

3

Cancer step 1

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

4

cancer step 2

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

5

cancer step 3

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

6

invasive

can invade healthy tissue cells

7

benign vs malignant

benign is noncancerous and malignant is cancerous

8

why don't all cells become cancer cells?

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

9

what are the go signals for the cell cycle?

cyclins and Cdks & they have a cyclic pattern

10

what stops cells from continually dividing?

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

11

What are the stop signals in the cell cycle?

checkpoints-- there are three

12

what are the three checkpoints ?

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)

13

Cell cycle control system is a combination ...

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

14

Cancer is uncontrolled cell division

1) activate positive regulators = oncogenes
2) inhibit checkpoint regulators = tumor suppressors

15

How to turn a proto-oncogene into an oncogene

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

16

Function of changing proto-oncogene into an oncogene

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

17

Loss of herterozygosity

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

18

two-hit model

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

19

two-hit model ways

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

20

Another two hit model

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

21

p53

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

22

dominant mutation

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

23

recessive mutation

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

24

cancer is usually...

a result of multiple genetic changes

25

metastasis

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

26

angiogenesis

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

27

COSMIC

catalog of somatic mutations in cancer

28

Hallmarks of cancer

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

29

Treat hallmark of sustained proliferation of cells

inhibit mitosis, block growth hormone receptors & inhibit kinases

30

Treat hallmark of evasion of growth suppressors

inhibit cell-cycle promoting proteins

31

Treat hallmark of avoid destruction by immune system

activate immune system (immunoncology)

32

Treat hallmark of immortality of cells

inhibit telomerase

33

Treat hallmark of cause tumor-promoting inflammation

some anti-inflammatories

34

Treat hallmark of activate metastasis

inhibit invasion of other tissues

35

Treat hallmark of angiogenesis

inhibit angiogenesis

36

Treat hallmark of genome instability

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

37

Treat hallmark of resist cell death

pro-apoptotic drugs

38

Treat hallmark of deregulate cellular energetics

aerobic glycolysis inhibitors

39

cancer is a disease characterized by ...

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

What makes a cell cancerous?

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

41

normal control of cell division

• 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

G2 checkpoint

check for cell size & DNA replication

43

Spindle Assemble Checkpoint

check for chromosome attachment to spindle

44

G1 checkpoint

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

45

Cancers arise when critical genes are mutated causing.. .

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

46

once malignant

the cells are invasive

47

cells have a great many defects by the time they ...

become cancerous

48

Cancer cells are clones of the initial cell gone bad

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

cancer has a clonal origin

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

50

cancer is a result of multiple mutations

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

51

tumor

a clonal group of cells that arose from a prerecessor

52

inherited predisposition

only 5-10% of cancers
BRCA1 or BRCA2 mutations lead to breast cancer

53

spontaneous or induced mutation

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

54

Model

a small # of initial mutations >>increased mutation frequency 'genetic instability' >> more mutations >>cancer

55

predisposition for developing cancer

often the result of being heterozygous for one of these genes

56

types of cancer-causing genes

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

57

tumor suprresor

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

58

proto-oncogene

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

repair genes

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

when p53 is on

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

61

the two hit hypothesis

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

62

sporadic cases

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

63

familial cases

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

consequence of two hit hypothesis

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

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

at the cellular level be recessive

66

proto-oncogenes act dominantly at the cellular level

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

tranformation

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

68

Oncogenes were found because of their
ability to “transform” cells

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

the most famous oncogene

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

Chromosomal rearrangements can result in cancer

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

strategies for battling cancer

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

immunotherapy

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

73

why genetics makes treatment so hard

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

polyclonal tumor

layers of mutation/expansion

75

treating a tumor like an infection

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

Bacterial infection

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

77

Fungal infection

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

78

cancer infection

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

79

Chemotherapies DNA as a target

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

80

Doxorubicin drug

fragment the DNA

81

Cisplatin drug

glue the strands together

82

Methotrexate drug

attack the supply chain

83

Taxol drug

prevent separation of replicated DNA

84

traditional chemotherapy

targets production and common manipulations of DNA

85

Side effects of Chemotherapy on any replenishing (stem) cell

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

Side effects of Chemotherapy on some other cell type

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

Chemotherapy success

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

why difference in success?

accessibility to cancerous cells
localized
regional invasion

89

Rational drug design

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

90

Leukemia (CML)

Gleevec treats it and has a high survival rate

91

other possible cancer treatment approaches

• 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

molecular profiling to classify tumors

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

cancer genome challenge

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