Cancer Genetics

Question 1

What are somatic mutations?

Answer 1

Where there is a genetic defect in a cell within a specific tissue that develops after birth

Question 2

What are oncogenes? How are they implicated in cancer?

Answer 2

‘On’ switch genes that promote cell growth in G1

Control genes regulate these ‘on’ switches by preventing cell growth after cell division has happened
Mutations in control genes can prevent oncogene from turning off, causing cell proliferation

Question 3

What are tumour suppressor genes?

Answer 3

‘Off’ switch genes that check whether cell is ready to enter S-phase and so can prevent proliferation

Question 4

Disruption to what type of gene, other than oncogene or tumour suppressor gene, can cause cancer?

Answer 4

DNA repair genes, because if they are not working they can’t repair mutations so they persist in the cell line

Question 5

How many copies/alleles of a mutated oncogene need to be present for cancer to develop?

Answer 5

One, because once the ‘on’ switch is on, cell proliferation occurs indefinitely

Question 6

Outline the Knudson’s Two-Hit Hypothesis

Answer 6

2 copies/alleles of a mutated tumour suppressor gene or DNA repair gene need to be present for cancer to develop

One mutation makes you susceptible because only the other needs to be disrupted

Two mutations lead to cancer

Question 7

What does the Knudson’s Two-Hit Hypothesis say about when cancer’s develop?

Answer 7

If you have inherited one mutation in a tumour suppressor gene/DNA repair gene, then since only one (not two) more copy needs to become mutated for you to get cancer, the age of onset of your cancer will be earlier

Late 50s compared to early 40s for breast cancer (the latter have familial BRCA1 and 2 genes)

Question 8

What % of breast cancer is genetic?

Answer 8

5-10%

Question 9

Chance of developing breast cancer with BRCA1 or 2 mutation?

Answer 9

85%

Question 10

What type of gene are BRCA1 and 2?

Answer 10

DNA repair genes

Question 11

What kind of cancers can BRCA1 and 2 mutations cause?

Answer 11

Breast cancer (male and female)
Ovarian cancer

Question 12

In a pedigree, when might you suspect a BRCA1 or 2 mutation?

Answer 12

Lots of breast (sometimes bilateral) and ovarian cancer (sometimes both in one individual)

Male as well as female

<50 age of diagnosis

Dominant inheritance

Jewish ancestry

Question 13

What are the two ways of breast screening?

Pros and cons of each?

Answer 13

Mammography

• cheaper
• uses radiation
• young women have denser breasts which show up white… the same colour as cancer

MRI screening

• expensive
• more sensitive in younger women

Question 14

Surgery to reduce risk of breast and ovarian cancer?

Answer 14

Mastectomy and reconstruction for breast cancer
-risk to <10%

Oophorectomy for ovarian cancer
-risk to <2%

Question 15

Treatment for BRCA1 or 2 carriers?
How good is it and why?
How do they work?

Answer 15

Possible treatment in PARP (poly-ADP ribose polymerase) inhibitors

Symptom free, effective

Cancer cells have a broken BRCA DNA repair pathway, so in order to not apoptose they go down the PARP DNA repair pathway
PARP inhibitors block this pathway as well, so cancer cell stops proliferating and apoptoses

Question 16

Inheritance of Familial Adenomatous Polyposis and Lynch syndrome?
What do these cause?

Answer 16

Both autosomal dominant

They both cause bowel cancer

Question 17

Where is the mutation in FAP?

Answer 17

The APC gene

Question 18

Which mutations cause Lynch syndrome?

Answer 18

MLH1, MSH2, MSH6, PMS2

Question 19

Inheritance of BRCA1 or 2?

Answer 19

Autosomal dominant

Question 20

What happens in FAP? Standard treatment?

Answer 20

Predisposition to bowel polyps - tend to develop during teenage years
Cancer is inevitable, usual onset is 20s

Treat surgically with colectomy

Question 21

What to look out for in pedigree for Lynch syndrome?

Answer 21

Multiple people with bowel cancer <60
One person with bowel cancer <45
People developing cancer twice
Presence of other cancers like endometrial, ovarian, stomach/small intestine

Question 22

Screening for bowel cancer?

Answer 22

Colonsocopy

Question 23

Which gene is mutated in Li-Fraumeni Syndrome, and what is it’s function? Inheritance?

Answer 23

P53 - tumour suppressor gene

Autosomal dominant

Question 24

Li-Fraumeni complications? Management?

Answer 24

Variety of different cancers seen and often childhood cancer
Basically individual very susceptible to developing cancer

Yearly total body MRI - open access to oncologists

Question 25

Mutation in MENIN causes? And RET? Inheritance?

Answer 25

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 2

Autosomal dominant

Question 26

Compare MEN1 and 2

Answer 26

MEN1 - Pituitary, pancreas and parathyroid tumours (3 Ps) —> usually benign

MEN2 - Medullary thyroid and paraythyroid cancers, as well as phaeochromocytoms —> usually malignant