Genetics- Cancer

Question 1

cancer

Answer 1

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

Question 2

what causes cancer?

Answer 2

caused by a series of genetic changes

Question 3

Cancer step 1

Answer 3

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

Question 4

cancer step 2

Answer 4

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

Question 5

cancer step 3

Answer 5

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

Question 6

invasive

Answer 6

can invade healthy tissue cells

Question 7

benign vs malignant

Answer 7

benign is noncancerous and malignant is cancerous

Question 8

why don’t all cells become cancer cells?

Answer 8

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

Question 9

what are the go signals for the cell cycle?

Answer 9

cyclins and Cdks & they have a cyclic pattern

Question 10

what stops cells from continually dividing?

Answer 10

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

Question 11

What are the stop signals in the cell cycle?

Answer 11

checkpoints– there are three

Question 12

what are the three checkpoints ?

Answer 12

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)

Question 13

Cell cycle control system is a combination …

Answer 13

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

Question 14

Cancer is uncontrolled cell division

Answer 14

1) activate positive regulators = oncogenes

2) inhibit checkpoint regulators = tumor suppressors

Question 15

How to turn a proto-oncogene into an oncogene

Answer 15

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

Question 16

Function of changing proto-oncogene into an oncogene

Answer 16

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

Question 17

Loss of herterozygosity

Answer 17

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

Question 18

two-hit model

Answer 18

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

Question 19

two-hit model ways

Answer 19

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

Question 20

Another two hit model

Answer 20

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

Question 21

p53

Answer 21

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

Question 22

dominant mutation

Answer 22

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

Question 23

recessive mutation

Answer 23

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

Question 24

cancer is usually…

Answer 24

a result of multiple genetic changes

Question 25

metastasis

Answer 25

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

Question 26

angiogenesis

Answer 26

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

Question 27

COSMIC

Answer 27

catalog of somatic mutations in cancer

Question 28

Hallmarks of cancer

Answer 28

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

Question 29

Treat hallmark of sustained proliferation of cells

Answer 29

inhibit mitosis, block growth hormone receptors & inhibit kinases

Question 30

Treat hallmark of evasion of growth suppressors

Answer 30

inhibit cell-cycle promoting proteins

Question 31

Treat hallmark of avoid destruction by immune system

Answer 31

activate immune system (immunoncology)

Question 32

Treat hallmark of immortality of cells

Answer 32

inhibit telomerase

Question 33

Treat hallmark of cause tumor-promoting inflammation

Answer 33

some anti-inflammatories

Question 34

Treat hallmark of activate metastasis

Answer 34

inhibit invasion of other tissues

Question 35

Treat hallmark of angiogenesis

Answer 35

inhibit angiogenesis

Question 36

Treat hallmark of genome instability

Answer 36

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

Question 37

Treat hallmark of resist cell death

Answer 37

pro-apoptotic drugs

Question 38

Treat hallmark of deregulate cellular energetics

Answer 38

aerobic glycolysis inhibitors

Question 39

cancer is a disease characterized by ...

Answer 39

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

Question 40

What makes a cell cancerous?

Answer 40

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

Question 41

normal control of cell division

Answer 41

``` • 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 ```

Question 42

G2 checkpoint

Answer 42

check for cell size & DNA replication

Question 43

Spindle Assemble Checkpoint

Answer 43

check for chromosome attachment to spindle

Question 44

G1 checkpoint

Answer 44

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

Question 45

Cancers arise when critical genes are mutated causing.. .

Answer 45

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

Question 46

once malignant

Answer 46

the cells are invasive

Question 47

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

Answer 47

become cancerous

Question 48

Cancer cells are clones of the initial cell gone bad

Answer 48

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

Question 49

cancer has a clonal origin

Answer 49

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

Question 50

cancer is a result of multiple mutations

Answer 50

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

Question 51

tumor

Answer 51

a clonal group of cells that arose from a prerecessor

Question 52

inherited predisposition

Answer 52

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

Question 53

spontaneous or induced mutation

Answer 53

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

Question 54

Model

Answer 54

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

Question 55

predisposition for developing cancer

Answer 55

often the result of being heterozygous for one of these genes

Question 56

types of cancer-causing genes

Answer 56

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

Question 57

tumor suprresor

Answer 57

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

Question 58

proto-oncogene

Answer 58

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)

Question 59

repair genes

Answer 59

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

Question 60

when p53 is on

Answer 60

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

Question 61

the two hit hypothesis

Answer 61

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

Question 62

sporadic cases

Answer 62

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

Question 63

familial cases

Answer 63

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

Question 64

consequence of two hit hypothesis

Answer 64

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

Question 65

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

Answer 65

at the cellular level be recessive

Question 66

proto-oncogenes act dominantly at the cellular level

Answer 66

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!

Question 67

tranformation

Answer 67

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

Question 68

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

Answer 68

``` 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 ```

Question 69

the most famous oncogene

Answer 69

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

Question 70

Chromosomal rearrangements can result in cancer

Answer 70

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

Question 71

strategies for battling cancer

Answer 71

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)

Question 72

immunotherapy

Answer 72

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

Question 73

why genetics makes treatment so hard

Answer 73

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

Question 74

polyclonal tumor

Answer 74

layers of mutation/expansion

Question 75

treating a tumor like an infection

Answer 75

``` 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 ```

Question 76

Bacterial infection

Answer 76

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

Question 77

Fungal infection

Answer 77

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

Question 78

cancer infection

Answer 78

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

Question 79

Chemotherapies DNA as a target

Answer 79

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

Question 80

Doxorubicin drug

Answer 80

fragment the DNA

Question 81

Cisplatin drug

Answer 81

glue the strands together

Question 82

Methotrexate drug

Answer 82

attack the supply chain

Question 83

Taxol drug

Answer 83

prevent separation of replicated DNA

Question 84

traditional chemotherapy

Answer 84

targets production and common manipulations of DNA

Question 85

Side effects of Chemotherapy on any replenishing (stem) cell

Answer 85

``` 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 ```

Question 86

Side effects of Chemotherapy on some other cell type

Answer 86

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

Question 87

Chemotherapy success

Answer 87

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

Question 88

why difference in success?

Answer 88

accessibility to cancerous cells localized regional invasion

Question 89

Rational drug design

Answer 89

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

Question 90

Leukemia (CML)

Answer 90

Gleevec treats it and has a high survival rate

Question 91

other possible cancer treatment approaches

Answer 91

• 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

Question 92

molecular profiling to classify tumors

Answer 92

``` 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! ```

Question 93

cancer genome challenge

Answer 93

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