11. Cancer genetics 3: DNA repair genes

Question 1

What are carcinogens?

Answer 1

DNA altering chemicals

Question 2

What kind of progression is cancer?

Answer 2

step wise

Question 3

How many cancer causing genes are there?

Answer 3

around 700 genes which is 2-3% of all human genes

Question 4

How many hits do oncogenes need?

Answer 4

generally only 1 mutated allele is needed to initiate cancer

Question 5

How many hits do tumour suppressor genes need?

Answer 5

need mutations in 2 alleles to contribute to cancer

Question 6

What are 3 statements that describe Knudson’s 2-hit theory?

Answer 6

1. it underpins the identification of tumour suppressor genes
2. it applies to the development of familial cancers
3. it applies to the tumour that arise from somatic mutations

Question 7

Why study cancer genetics: family planning

Answer 7

It is used to predict the likelihood the offspring will have the mutation and gives people more information when they are starting a family

Question 8

Why study cancer genetics: prophylactic prevention

Answer 8

Removal of the at risk tissue like a mastectomy when the patient has a BRCA1/2 mutation

Question 9

Why study cancer genetics: insights into aetiology

Answer 9

It helps provide insight into the cause of the cancers in general and of a specific cancer. Applies to both sporadic and inherited cancers

Question 10

Identification of predisposing genes: linkage analysis

Answer 10

1. Used to trace the pattern of disease through high risk families
2. Use these as a way to identify genetic markers and co-inherited regions
3. Use the link between these markers and cancer

Question 11

Identification of predisposing genes: karyotypes

Answer 11

Use to see the chromosomes and identify:
1. translocations
2. large deletions
3. aneuploidy
4. polyploidy
5. truncations

Question 12

Identification of predisposing genes: allele loss studies to find loss of heterozygosity

Answer 12

1. normally 2 bands for 2 different alleles
2. only 1 band can indicate a loss of 1 allele and therefore heterozygosity

Question 13

Identification of predisposing genes: whole genome sequencing

Answer 13

1. taking advantage of recent technology
2. sequence the whole genome and map to a reference genome
3. has been used to identify TSGs like B-raf

Question 14

What are primary causes of cancer?

Answer 14

1. they have direct involvement in the development of cancer
2. oncogenes
3. TSGs

Question 15

What are indirect causes of cancer?

Answer 15

1. Genes that are not directly involved in causing cancer but they play a role
2. DNA repair genes that without function mutations will accumulate
3. Carcinogen metabolism genes which convert metabolite to carcinogens or visa versa

Question 16

Why are DNA repair genes important in cancer development?

Answer 16

1. when they work properly they can repair DNA damage and prevent them becoming mutations
2. aid cell survival
3. If the repair is unsuccessful it kills the cell to prevent passing on mutations
4. If these repair mechanisms don’t work that mutations accumulate and contributes to cancer

Question 17

What are the ways DNA can be damaged?

Answer 17

1. Reactive oxygen species
2. UV light
3. Smoking and other bulking DNA products
4. modifications of bases like alkylation
5. DNA replication mistakes

Question 18

How can DNA damage be repaired?

Answer 18

1. nucleotide excision repair
2. base excision repair
3. Mismatch repair

Question 19

When does DNA need to be repaired?

Answer 19

before replication takes place and the cell proliferates

Question 20

What happens if DNA is not repaired properly?

Answer 20

Accumulation of mutations

Question 21

What can DNA damage fingerprinting help do?

Answer 21

1. help identify what caused the cancer
2. currently over 97 distinct signatures for different carcinogens

Question 22

What is Ataxia telangiectasia?

Answer 22

1. A rare, autosomal recessive disease caused by ATM mutation
2. effects the cerebellum so effects co-ordination - ataxia
3. telangiectasia = dilated capillaries
4. immune deficiency
5. highly sensitive to ionising radiation like sunlight and X-rays
6. risk of leukaemia and lymphoma
7. Heterozygotes have increased cancer risk

Question 23

What causes Ataxia telangiectasia?

Answer 23

Mutation in ATM

Question 24

What is ATM?

Answer 24

1. A protein that senses DNA damage especially dsDNA breaks
2. Kinase activity
3. ATM activates CHK2 to arrest the cell cycle in the S phase
4. also activates p53 to arrest the cell cycle at the G1 checkpoint

Question 25

What happens in cells with ATM mutations?

Answer 25

1. cell cycle is not arrested and the mutations accumulate and are passed on to the daughter cells
2. cellular catastrophe
3. more dsDNA breaks
4. mitotic catastrophe that leads to weird things like 3 daughter cells after mitosis

Question 26

What is Xeroderma pigmentosa?

Answer 26

1. A rare autosomal recessive disorder
2. features include dwarfism, intellectual disability, blindness, deafness
3. Severe UV sensitivity and early onset skin cancers, XP patients have exponential risk early in life
4. mutations in genes involved in DNA excision repair so mutations accumulate over time

Question 27

What is bloom syndrome?

Answer 27

1. A DNA helicase deficiency due to mutation in BLM gene that helps in DNA helicase production
2. not optimal DNA replication leading to more errors

Question 28

What is Fanconi anaemia?

Answer 28

1. Mutations in over 20 genes in the homologous recombination pathway
2. each protein is involved in recruiting the others so if one is defective then the recruitment doesn’t happen and repair fails
3. causes: anaemia, intellectual disability, skeletal abnormalities, leukaemia

Question 29

What is an example of a Fanconi gene?

Answer 29

1. BRCA 2
2. Causes falcon anaemia, childhood tumours, ovarian cancer, breast cancer
3. some genes are more important in predisposing to certain cancer like BRCA1/2 and breast cancer

Question 30

What are microsatellite repeats?

Answer 30

1. short repeated sequences in the DNA
2. makes it harder for the cell to replicate and causes lots of errors
3. located near coding regions

Question 31

What is microsatellite instability?

Answer 31

1. When the microsatellites are mis replicated caused by a deficiency in mismatch repair.
2. very common in cancers

Question 32

What is hereditary non-polyposis colon cancer?

Answer 32

1. lynch syndrome
2. autosomal dominant
3. mutations in mismatch repair genes which cause errors in the DNA
4. early onset colon cancer
5. eg MLH1, MSH2, MSH6, PMS1, PMS2

Question 33

What can mismatch repair defects cause?

Answer 33

TGFß receptor loss

Question 34

what does TGFß receptor loss cause?

Answer 34

1. truncated receptors caused by a frame shift mutation and a premature stop codon
2. receptors are degraded
3. TGFß cannot bind
4. TGFß cannot prevent cell proliferation
5. results in uncontrolled growth

Question 35

What is the function of TGFß?

Answer 35

1. inhibits cell growth by binding to its receptor
2. TGFß receptor is a serine/threonine kinase receptor

Question 36

Carcinogen metabolism: initiation

Answer 36

1. starts the process of mutagenesis
2. caused by a carcinogen
3. irreversible cell damage
4. this itself cannot cause cancer

Question 37

Carcinogen metabolism: promotion

Answer 37

1. supports the proliferation of the initiated cells
2. can be reversible in the early stages
3. you can only promote an initiated cell

Question 38

Carcinogen metabolism: progression

Answer 38

1. development of more malignant features
2. more mutations

Question 39

What can some carcinogens be?

Answer 39

both initiators and promoters

Question 40

What are pro-carcinogens?

Answer 40

Chemicals/compounds that need to be metabolised by the body to become carcinogens

Question 41

What is an example of an enzyme that metabolises carcinogens?

Answer 41

1. cytochrome P450 enzymes like CYP2D6
2. usually hydroxylate bases
3. people with more of these enzymes have higher risk of some cancers suggesting they have a role in converting pro-carcinogens