Basic mechanisms in cancer biology

Question 1

What is cancer?

Answer 1

Uncontrolled cellular growth

Question 2

Possible issue with calling cancer “uncontrolled cell growth”?

Answer 2

Could be positive–>cell may pick up asn advantageous mutation and then do uncontrolled cell growth

Question 3

Key properties of cancer cells?

Answer 3

Ability to replicate indefinitely, Ability to evade apoptosis

Question 4

What kind of mutations could accelerate the early development of some cancers?

Answer 4

Mutations that inactivate DNA repair pathways, and mutations that increase the rate of cell division

Question 5

What is a stem cell?

Answer 5

Cell types that can self renew or differentiate into a specialised cell type

Question 6

What type of stem cell does each organ/tissue have?

Answer 6

One that is specific to the organ/tissue itself i.e. the brain will have stem cells that can differentiate into each type of neuron and any other brain cells

Question 7

What is similar between stem cells and cancer cells?

Answer 7

The ability to replicate themselves indefinitely

Question 8

What could happen to a stem cell to cause it to become a cancer stem cell?

Answer 8

If a mutation inactivated a DNA repair pathway, the cell would be able to pick up mutations fairly quickly

Question 9

Why should cancer stem cells be a target for chemotherapeutic strategies?

Answer 9

Many cytotoxic agents would kill the tumour cells but leave the stem cells, meaning a relapse may occur

Question 10

Why does cancer relapse sometimes?

Answer 10

The cytotoxic agents kill the tumour cells but the cancer stem cell survives, meaning the tumour can come back

Question 11

What is an oncogene?

Answer 11

A gene that, when activated in a particular way, will promote cancer formation

Question 12

What kind of mutation usually happens to an oncogene?

Answer 12

A gain of function mutation

Question 13

What kind of mutation (dom/rec) usually happens to an oncogene?

Answer 13

Dominant

Question 14

Why do oncogene mutations usually occur with no family history?

Answer 14

They only need to occur in a single copy of the geneas they are usually dominant mutations

Question 15

What is a chromosomal translocation?

Answer 15

When two chromosomes swap portions of genetic material

Question 16

What is the philadelphia chromosome?

Answer 16

When a short part of chromosome 9 is translocated onto a short part of chromosome 22

Question 17

What gene from chromosome 9 is at the break point when the philadelphia chromosome is formed?

Answer 17

ABL gene

Question 18

What gene from chromosome 22 is at the break point when the philadelphia chromosome is formed?

Answer 18

BCR gene

Question 19

What happens on the philadelphia gene?

Answer 19

A fusion gene (BCR/ABL) gene is present

Question 20

What is the role of the Abl gene?

Answer 20

It is a regulator of hematopoietic cell division

Question 21

What happens to the Abl gene in the philadelphia chromosome?

Answer 21

It is locked into the “on” position

Question 22

What happens as a result of the Abl gene being locked “on” in the philadelphia chromosome?

Answer 22

Uncontrolled hematopoietic cell division

Question 23

What is a consequence of uncontrolled hematopoietic cell division?

Answer 23

Leukaemia

Question 24

What is the function of the MYC gene?

Answer 24

It is a transcription factor that interacts with another transcription factor called Max

Question 25

What do MYC and Max form?

Answer 25

A heterodimer

Question 26

What does the Max-MYC heterodimer bind to?

Answer 26

They bind to an E box element (CACGTG)

Question 27

What is the importance of the CACGTG E box element?

Answer 27

It is a promoter that can be found upstream of cell growth regulator genes

Question 28

What happens when the MYC gene is mutated/amplified?

Answer 28

There is an overactivation of the genes that drive proliferation of early neural cells

Question 29

Where do tumours form as a result of a MYC amplification?

Answer 29

The sympathetic nervous system--> neuroblastoma

Question 30

What is a tumour suppressor gene?

Answer 30

A gene who carries out a function that suppresses tumour formation

Question 31

What is biallelic inactivation?

Answer 31

Both genes need to be inactivated by mutation

Question 32

Familial effect on tumour suppressor genes?

Answer 32

Associated cancers can more commonly display a family history

Question 33

What is knudsons two hit hypothesis

Answer 33

For sporadic cases, there is no inherited mutations so both mutations would need to occur on the same gene in the same cell

Question 34

Knudsons two hit hypothesis (but one hit)?

Answer 34

If one of the gene mutations is inherited, only one "hit" (mutation) would need to occur

Question 35

Why are familial cases of TSG inactivation more common?

Answer 35

More likely that one mutation is inherited and one occurs during life than both mutations occuring during life

Question 36

What are the major human breast cancer susceptibility genes?

Answer 36

BRCA1 and BRCA2

Question 37

What is a DNA double strand breakage?

Answer 37

A break in the phosphodiester backbone on both strands of the DNA backbone

Question 38

Effect of a double strand break on the DNA?

Answer 38

Can cause a section of damaged DNA to go missing

Question 39

Issue with the Non-Homologous End Joining (NHEJ) method of fixing DNA?

Answer 39

It just connects the two ends of DNA, and doesn't take into account the section that has gone missing

Question 40

What is a better method of fixing a double stranded DNA break?

Answer 40

Homologous recombination

Question 41

How does homologous recombination work?

Answer 41

Enzyme resects DNA, exposes a single stranded region. Single stranded region then looks for section of homologous chromosome that has sequence homology to it. That is then used to figure out what the missing section is

Question 42

Benefit of homologous recombination?

Answer 42

The section of DNA that went missing is replaced in the fixed DNA

Question 43

What does BRCA1 do?

Answer 43

Senses the DNA break and recruits BRCA2

Question 44

What does BRCA2 do?

Answer 44

Recruits RAD51 and loads it onto the single stranded region

Question 45

What does RAD51 do?

Answer 45

RAD51-single strand complex is required for strand invasion process (from homologous recombination)

Question 46

What can mutations in BRCA2 cause (other than breast cancer)?

Answer 46

Fanconi's anemia--> associated w/ bone marrow failure and leukaemia

Question 47

How does the mutated BRCA2 work to get breast cancer?

Answer 47

One mutation is inherited from parents, while the other mutation occurs during life

Question 48

How does the mutated BRCA2 work to get Fanconi's anemia?

Answer 48

Both mutations are inherited from parents

Question 49

Symptoms of Von Hippel-Lindau syndrome?

Answer 49

Fatigue, poor motor coordination and vision impairment

Question 50

What kind of condition (dom/rec) is VHL?

Answer 50

Dominant condition, so only one copy of the gene needs to mutate

Question 51

Differences in VHL syndrome depending on if you have one or both copies of the gene mutated?

Answer 51

There are different sets of symptoms for VHL

Question 52

Normal role of VHL protein?

Answer 52

interacts w/ HIF-alpha transcription factor, causes it to be polyubiquitinated--> leads to degradation of HIF-alpha

Question 53

HIF-Alpha under hypoxic conditions?

Answer 53

VHL doesnt bind to it, instead HIF-alpha binds to HIF-beta--> this complex can turn on genes that are involved in angiogenesisW

Question 54

What is angiogenesis?

Answer 54

Blood vessel formation

Question 55

What causes VHL syndrome?

Answer 55

VHL protein never binds to HIF-alpha so overstimulation of angiogenesis (it will occur in normal conditions a well as in hypoxic ones)