17: The molecular basis of cancer

Question 1

Why does cancer become more prevalent as population ages?

Answer 1

live longer = more exposure to mutagens (smoke, sun, virus, radiation) = more mutations accumulated = higher chance to acquire cancer

Question 2

What are cancer risk factors?

Answer 2

smoking, drinking, obesity

Question 3

What is the molecular basis of cancer?

Answer 3

genetic mutations in DNA that cause biochemical defects

Question 4

What are the types of mutations?

Answer 4

somatic/autosomal: mutation from birth

acquired: smoking, risk factor exposure, random mutagenesis, DNA damaging agents

Question 5

How do we know that cancer is a genetic disease?

Answer 5

Susceptibility to cancer can be inherited
(This doesn’t mean an individual will get cancer, but may increase chances)

Question 6

Why is DNA damage so significant?

Answer 6

RNA and protein can be replaced, but DNA must be preserved

Question 7

Why is the cancer acquirement selected against for juvenile cancer?

Answer 7

no selective pressure against elderly getting more mutations bc they are past the reproducing age

Question 8

Why do we have DNA polymerase that makes mistakes?

Answer 8

variability is required for evolution

Question 9

What is the error rate in DNA replication? Why is is actually lower?

Answer 9

~1 in 10,000 bases synthesized

actually lower bc DNA poly proofreads and fixes some AND error could be in non-coding regions (part of protein that will not limit function)

Question 10

What is the most common mutagen?

Answer 10

cigarette smoke: 69 chemicals known to cause cancer

Question 11

avoidable causes of cancer?

other causes of cancer?

Answer 11

1. DNA damaging agents (radiation, UV, x-rays, chemical mutagens)
2. ## viruses (vaccines)
3. genetics
4. replication errors

Question 12

is a single mutation is sufficient to cause cancer? why?

Answer 12

usually no

Tumour progression involves successive rounds of mutation and selection (evolution) and each round of replication acquires another mutation allowing it to grow faster or in abnormal places (selection for where most successful at dividing)

also

eukaryotes have many checkpoints to stop for repair, cell cycle control, apoptosis genes

Question 13

What are the 4 characteristics pf cancer cells?

Answer 13

1. Divide in the absence of growth factor signals
2. Are immortal = Do not respond to signals that normally trigger cell death
3. Have lost cell cycle control/can’t stop replication and cells don’t stop at normal cell cycle checkpoints
4. Cancer cells are genetically unstable
5. Cancer cells multiply in abnormal places (metastasize)

Question 14

why are cancer cenlls genetically unstable?

Answer 14

• prone to point mutations bc they are not selected against (cancer cells don’t cause point mutations)
• cells can grow where they normally wouldn’t be able to grow
• these abnormalities are kept by cells bc they don’t follow checkpoints

Question 15

What are the two main categories of cancer causing genes?

Answer 15

1. oncogenes
2. tumour suppressor genes

Question 16

What are ONCOGENES?

Answer 16

A mutant form of a normal gene whose presence causes cancer

this is a gain of function; cells do something/are active incorrectly

Question 17

How do oncogenes form?

Answer 17

normal cell containing normal gene (proto-oncogene) –> single mutation event –> oncogene created

Question 18

What types of genetic change can result in an oncogene?

Answer 18

1. Mutation in protein encoding region amounts
2. Gene Amplification
3. Chromosomal Rearrangement

Question 19

What does a Mutation in protein encoding region cause?

Answer 19

no change in amount of protein made, protein is in hyperactive form made in normal

type of genetic change causing oncogene

Question 20

What does gene amplification cause?

Answer 20

no oncogene, more copies of same gene in genome, normal protein overproduced

type of genetic change causing oncogene

Question 21

What does chromosomal rearrangement cause?

Answer 21

1. gene moved to different promoter region causing gene amplification: high expression of normal gene
2. gene transcribed as a fusion with another protein causing hyperactive fusion protein

type of genetic change causing oncogene

Question 22

What are Tumour suppressors?

Answer 22

A gene whose absence causes cancer. (recessive, loss of function)

Question 23

How do Tumour suppressor genes form?

Answer 23

normal cell –> mutation event inactivates tumor suppressor gene –> no effect of mutation in one gene copy –> second mutation event inactivates second gene copy –> two inactivating mutations

Question 24

What is the target of cancer causing gene?

Answer 24

Most oncogenes and tumour suppressors code for proteins that act in or regulate cell division or cellular differentiation

Question 25

How do cancer causing genes target **growth factors and cellular receptors** for growth?

Answer 25

normal: growth factor binds to cellular growth receptors so that the latter is activated (conformation change) and causes cell division mutated cellular grwoth receptor: unbound cellular receptor is always on due to conformation change that sugnals activation = cell continously divides

Question 26

How do cancer causing genes target **molecules** involved in **cell-cell interactions**?

Answer 26

* Cell-cell interactions regulate normal growth and signal differentiation * If these are lost cells continue to divide when they should not.

Question 27

How do cancer causing genes target regulators of **apoptosis**?

Answer 27

Cancer cells do not respond to the normal signals that trigger cell death due to tumour suppressor (p53) mutation p53 senses stressors, stops cell at checkpoint and signals for apoptosis or fixing

Question 28

How do cancer causing genes target regulators of **Transcription** **factors** ?

Answer 28

Cancer can be caused by too much or too little expression of the genes that regulate cell growth, differentiation or cell death | can be tumour suppressors or oncogenes at the same time

Question 29

How do cancer causing genes target regulators of **DNA repair proteins**?

Answer 29

Cells accumulate more and more DNA damage and thus mutations to key genes

Question 30

What is **Xeroderma pigmentosum (XPC)**? What is the mechanism and cause?

Answer 30

DNA Repair Deficiencies causing skin cancer: Melanomas develop from exposure of the skin to the UV rays of the sun which cause pyrimidine dimers in DNA that can't be fixed

Question 31

What is the cause of breast cancer?

Answer 31

tumour suppressors BRCA1/2 mutation inherited; BRCA 1 mutation = ds breaks repair deficiency - NHEJ (if both are mutated this is worse)

Question 32

What are the classic cancer treatment options?

Answer 32

1. surgery 2. radiation 3. chemotherapy

Question 33

What is the surgery/radiation mechanism for treating cancer?

Answer 33

* Stops cells from replicating by severely damaging DNA * location specific * difficult to gt all of cells, so the remaining proliferate * radiation is targeted and doesn't damage other tissues

Question 34

What is the chemotherapy mechanism for treating cancer?

Answer 34

Stop cells from replicating by damaging DNA or interfering with the mitotic machinery or reducing replication substrates so cancer cells die from not having enough DNA/too much DNA damage to be viable target cells that divide fast so that other cells can repair themselves but cancer cells can't | exposes entire body

Question 35

What is the breast cancer treatment mechanism?

Answer 35

* BRCA 1 mutant = no ds repair * PARP 1 mutant = no ss repair * give PARP 1 inhibitor to BRCA 1 mutated cell bc this causes cell death

Question 36

Why is cancer treatment difficult?

Answer 36

1. **Cancer cells develop resistance to the drug** – Cells overexpress transporters that pump out the drugs (efflux) **2. Tumours are Heterogeneous** – The cancerous cells are always “evolving” (they change with time), so in one mass of cancerous cells, some are drug reisitant, some are more mutated **3. Specificity of the treatment** – Radiation and classic chemotherapy treatments also affect normal cells (x-rays, parp 1 inhibitor effects cells without BRCA 1 mutations) **4. Different cancers have different underlying causes** **5. adding antibiotics selects for more resistance**

Question 37

What are the goals of modern cancer treatment?

Answer 37

* Earlier detection *Greater drug specificity * Combination therapies * Identifying drugs for the “undruggable” targets * Profiling cancer cell genomes * Prevention