13.4 Cancer

Question 1

What are somatic mutations?

Answer 1

• Acquired
• Present in only some cells

Question 2

What structure is somatic tumour genetic testing conducted on? Why is this testing conducted?

Answer 2

• Tumour tissue
• Diagnostic/treatment purposes

Question 3

List some hallmarks of cancer

Answer 3

• Angiogenesis
• Avoiding immune destruction
• Invading surrounding tissues
• Replicative immortality

Question 4

What percentage of cancers are acquired over a person’s lifetime

Answer 4

95%

Question 5

What is an adenoma?

Answer 5

Benign tumour

Question 6

What is a carcinoma?

Answer 6

Cancerous tumour

Question 7

Does activation or inactivation of tumour suppressor genes increase cancer risk? What is this known as?

Answer 7

Inactivation (like the brakes on a car)
“Loss of function”

Question 8

Does activation or inactivation of proto-oncogenes decrease cancer risk? What is this termed?

Answer 8

Activation (PROTOtype -> dodgy and doesn’t work as designed)

“Gain of function”

Question 9

What are the two categories of tumour suppressor genes?

Answer 9

• Gate-Keeper Genes
• Care Taker Genes

Question 10

What are Gate Keeper Genes Responsible for?

Answer 10

• Cell cycle regulators
• Checkpoint control
• Apoptosis-related
  (gatekeep growth)

Question 11

What are care taker genes responsible for?

Answer 11

• DNA repair
• Cellular maintenance
  (take care of genetic stability)

Question 12

Which gene encodes the p53 protein?

Answer 12

TP53

Question 13

Describe the action of the p53 protein in response to DNA damage

Answer 13

• Detects DNA damage
• Arrests cell cycle
• If repairable: repair
  else: apoptosis

Question 14

Describe driver mutations in cancer formation. What do they do, and what are they targets for?

Answer 14

• Directly responsible for cancer development
• Allow growth/replication, assist in apoptosis resistance etc.
• Potential therapy targets

Question 15

Describe passenger mutations in cancer development

Answer 15

• Not responsible for cancer formation
• BUT… not random; provide “genetic” scars that could indicate how the cancer came about

Question 16

What is tumour mutational burden?

Answer 16

The frequency of somatic mutations found in conjunction with a certain type of cancer

Question 17

What are genetic mutational signatures?

Answer 17

Characteristic combinations of mutations, often corresponding to types of cancer

Question 18

What can be the cause of “silent” cancers?

Answer 18

• Single oncogenic driver mutation
• Fusion driven cancers
• Chromosomal rearrangement driven cancer
• Epigenetic mutaions

Question 19

Can somatic epigenetic mutations influence someone while they are in utero?

Answer 19

Yes; like in the Dutch Hunger Winter

Question 20

What is the utility of germline genetic testing?

Answer 20

Risk determination

Question 21

Do one or both copies of a tumour suppressor gene need to be lost in order for loss of function to occur?

Answer 21

Both copies (homozygous)

Question 22

Do one or both copies of a proto-oncogene need to be activated in order for gain of function to occur?

Answer 22

Only one copy (heterozygous)

Question 23

Describe Knudon’s two-hit hypothesis

Answer 23

• Most non-hereditary mutations require both copies of a tumour suppressor gene to become mutated
• In the case of germline mutations, only one mutation is required to cause an effect, leading to predisposition

Question 24

Why can’t we directly extrapolate genotype to phenotype?

Answer 24

Because other environmental and genetic factors are present that affect the expression of genes

Question 25

Describe autosomal dominant inheritance

Answer 25

• Model of inheritance where only one copy of a mutated allele is required to pass on a condition/susceptibility to a child
• If one parent has one mutated allele, child has 50% chance of having it too

Question 26

What percentage of cancer predisposition arises from autosomal dominance?

Answer 26

1%

Question 27

Do autosomal dominant cancer inheritance patternss often produce non-cancer phenotypic features?

Answer 27

Not usually

Question 28

What is meant by “variable expressivity” in terms of autosomal dominant cancer inheritance?

Answer 28

Types of cancer in individuals with the same predisposition may vary

Question 29

What is Li-Fraumeni Syndrome?

Answer 29

Germline heterozygous pathogenic variant in TP53

Question 30

What does Li-Fraumeni predispose a person to?

Answer 30

• Breast cancer
• Brain cancer
• Gastric cancer

Question 31

What is autosomal recessive inheritance?

Answer 31

Both copies of a gene must be mutated in order for offspring to receive a condition/predisposition

Question 32

Do autosomal dominant/recessive inheritance mostly cause childhood/adulthood cancer?

Answer 32

Dominant: adulthood
Recessive: childhood

Question 33

Which of autosomal dominant/recessive inheritance typically cause non-cancer phenotypic features?

Answer 33

Dominant: Don’t
Recessive: Do

Question 34

Which genetic pathways are most commonly affected by autosomal recessive inheritance?

Answer 34

DNA pathway genes -> chromosomal instability

Question 35

In which germline-inherited situation is increased risk of cancer more mutation-specific: proto-oncogene activation or tumour suppressing gene deactivation?

Answer 35

Proto-oncogene activation (heterozygous). Very dependent on the specific mutation that is inherited through germline cells in proto-oncogenes.