Genetic Mechanisms in Cancer

Question 1

What tissues are ectoderm?

Answer 1

Skin, nervous tissue

Question 2

What tissues are mesoderm?

Answer 2

Muscles, bone, urogenital, blood

Question 3

What tissues are endoderm?

Answer 3

Digestive, respiratory

Question 4

80-90% of cancers are from ecto/endoderm. What are they called and where are they?

Answer 4

Carcinomas. Arise from epithelial cells in skin, lung, breast, pancreas

Question 5

1% of cancers are sarcomas. What tissues are these from?

Answer 5

Mesodermal tissues - mesenchymal, connective tissue, bone, muscle, fat

Question 6

Haem cancers are 10% of cancers. Name some types and what tissue germ layer is this from?

Answer 6

Lymphoma, leukaemia, myeloma - mesoderm.

Question 7

What’s the most common of all cancers? It’s a type of carcinoma. And what percentage?

Answer 7

Skin cancer, 30% of all cancers

Question 8

What’s the breakup of skin cancers:
75% -
20% -
1% -

Answer 8

The breakup of skin cancers:
75% - basal cell
20% - squamous cell
1% - melanoma

Question 9

What are some of the most common carcinomas?

Answer 9

Skin, lung, breast, colorectal, prostate

Question 10

How many subtypes of carcinoma are there?

Answer 10

200

Question 11

Radiation like UV typically causes skin cancer through what mechanism?

Answer 11

UV induces covalent bonds between adjacent pyramidines, these are misrepaired causing C>T transitions

Question 12

Smoking causes lung cancer through what mechanism?

Answer 12

Polycyclic aromatic hydrocarbons causing C>A Transitions

Question 13

Viruses cause 15-20% of cancers, name 3 viruses that do this

Answer 13

EBV, HPV, Herpes

Question 14

What percentage of cancers are from inherited predisposition?

Answer 14

5-10%

Question 15

What other things can cause cancer?

Answer 15

Lifestyle, hormones, chronic inflammation, chemical carcinogens etc. age

Question 16

What is a mutation signature?

Answer 16

The combination of mutations that are common for a given mutagen

Question 17

Cancers tend to have more mutations if what?

Answer 17

They are later onset, just due to age and the accumulation of mutations

Question 18

It’s harder to identify the driver mutations in what cancers?

Answer 18

The older onset ones due to the accumulation of mutations, whereas child onset ones like rhabdoid tumours have fewer.

Question 19

Name an oncogene in each category:
Positive growth regulator -
Signal Transduction -
Transcription Factors -
Cell Cycle Regulators -

Answer 19

Name an oncogene in each category:
Positive growth regulator - PDGF-R
Signal Transduction - Ras
Transcription Factors - MYC
Cell Cycle Regulators - Cyclins/CDK

Question 20

Name a Tumour Suppressor in each category:
Transcription factors -
Negative Growth Regulators -
DNA Repair Genes -

Answer 20

Name a Tumour Suppressor in each category:
Transcription factors - TP53
Negative Growth Regulators - PTEN (30-50% of cancers)
DNA Repair Genes - BRCA1, BRCA2, MSH1

Question 21

Which chromatin remodelling complex is important in several cancers? What percentage of cancers?

Answer 21

SWI/SNF. 20%

Question 22

What genes does SWI/SNF regulate expression for?

Answer 22

It regulates the expression of many genes for neural differentiation, embryonic stem cell differentiation, hepatic liquid metabolism, glucose metabolism.

Question 23

What are first and second hits normally?

Answer 23

First hit might be the loss of genetic material like a deletion. Then there’s a second hit be a loss through mitotic recombination so you lose your heterozygosity, or some inactivating SNV or deletion

Question 24

What is microsatellite instability?

Answer 24

When MMR is deficient, tandem repeats of 1-6bp expand or contract from faulty DNA repair.

Question 25

What epigenetics can cause cancer?

Answer 25

Hypermethylation of a tumour suppressor or hypomethylation of a proto-oncogene

Question 26

How can you detect loss of heterozygosity/mitotic recombination in tumours?

Answer 26

Use a matched blood and tumour sample. Then use high density SNP arrays, Array CGH, or low pass WGS. Copy number will stay the same but BAF will be 0.

Question 27

What happens after a first and second hit?

Answer 27

An accumulation of additional somatic mutations.

Question 28

Meningiomas are 1/3 of brain tumours with how many histological subtypes?

Answer 28

15

Question 29

In a Meningioma case the three tumour all had monosomy 22 which contains what?

Answer 29

NF2, which is commonly disrupted in meningiomas

Question 30

In the Meningioma case what was seen between her grade I, II and III tumours?

Answer 30

A progressive LOH of various regions as the grade increased. And an acquisition of mutations in the TERT promoter and ARID1A.

Question 31

What percentage of CRC has MSI?

Answer 31

15%

Question 32

What does MSI suggest in a tumour?

Answer 32

MMR not working

Question 33

A sporadic cause of MSI in CRC is what hypermethylation?

Answer 33

The promoter of MLH1

Question 34

CRC tumours with MSI have better prognosis than those without, true or false?

Answer 34

True

Question 35

20% of the time MSI CRC is caused by what?

Answer 35

Lynch syndrome (or HNPCC), the other 80% is sporadic

Question 36

Mutations in Lynch syndrome are generally in which genes?

Answer 36

MLH1, MSH2, MSH6 and PMS2

Question 37

Sometimes there are heritable epimutations, explain

Answer 37

A haplotype that is resistant to reprogramming, or inheriting a variant that causes methylation to be re-established in development.

Question 38

BRCA1 promoter methylation is in X% of sporadic breast cancer, as well as inherited BRCA1 variants

Answer 38

10% of sporadic breast cancer

Question 39

Hypermethylation of the BRCA1 promoter when present can be seen in every germ layer, true or false?

Answer 39

True

Question 40

Heritable epimutations are a rare mechanism but are found in multiple ________

Answer 40

Heritable epimutations are a rare mechanism but are found in multiple cancer syndromes

Question 41

What is Kataegis in some cancers?

Answer 41

The regional clustering of substitution variants. 6 or more with an average inter-mutation distance of <1kb.

Question 42

Where do Kataegis mutations cluster?

Answer 42

Open chromatin, transcription start sites

Question 43

What is likely to cause Kataegis?

Answer 43

Aberrant expression of APOBEC

Question 44

Kataegis is in what percentage of breast cancers?

Answer 44

55%

Question 45

Breast cancers with Kataegis are more likely to have what?

Answer 45

TP53 variants. Be estrogen negative, progresterone negative, HER2 positive. So less likely to have hormone therapy.

Question 46

Breast cancers with Kataegis are more likely to be...

Answer 46

Higher grade, and thus poorer survival. Generally older presentation though.