Genetic Aspects of Cancer

Question 1

What are the 4 properties needed for cells to become cancerous?

Answer 1

1. Proliferative signalling
2. Avoidance of apoptosis
3. Bypassing replicative senescence
4. Insensitivity to anti-growth signalling

Question 2

What 3 types of gene are involved in hereditary cancer?

Answer 2

1. Tumour suppressor genes
2. Proto-oncogenes
3. Stability/caretaker genes

Question 3

Define “tumour suppressor genes”.

Answer 3

Genes which are normally involved in inhibition of cell cycle, promotion of apoptosis or DNA repair; which, when affected by loss of function mutations, cause cancer

Question 4

Define “proto-oncogenes”.

Answer 4

Genes which are normally involved in stimulation of cell cycle and cell division, as well as response to growth factors; which, when affected by activation mutations, cause cancer

Question 5

Define “stability/caretaker genes”.

Answer 5

A type of tumour suppressor gene which is involved in DNA repair

Question 6

List the 3 types of tumour suppressor genes.

Give some examples of each.

Answer 6

Inhibiting cell cycle progression:
Rb gene
tp53 gene
NF1 gene

Promoting apoptosis:
tp53 gene
BAX gene

DNA repair:
90+ types of gene

Question 7

How do the following types of genes cause cancer?

a) Tumour suppressor genes
b) Proto-oncogenes
c) Stability/caretaker genes

Answer 7

TSGs:

1. Loss of function mutations make them switch off
2. Both copies of the TSG gene must be lost

PROTO-ONCOGENES:

1. Activation/gain of function mutations switch them on
2. Only one copy needs to be lost

STABILITY GENES:

1. Loss of function mutation
2. Both copies of the stability gene must be lost

Question 8

Outline Knudson’s two hit hypothesis.

Give 2 examples of inherited cancer which follows this theory.

Answer 8

1. A mutation in one copy of a TSG is passed on via autosomal dominant inheritance
2. A subsequent somatic mutation of the remaining normal gene is needed to cause cancer

EXAMPLES:
BRCA1 and 2
MEN1 (multiple endocrine neoplasia)

Question 9

Which clinical features would indicate that a particular cancer is familial, rather than sporadic? Consider:

a) Aspects of the family history.
b) Aspects of the individual case.

Answer 9

FAMILY HISTORY:

1. More than one affected individual in familiy
2. Similar cancers present (e.g. breast and ovarian)
3. Early onset

INDIVIDUAL:

1. Multiple primary tumours
2. Early onset

Question 10

Give 4 examples of genes which are involved in hereditary breast cancer.

Which BRCA mutation is more likely if:

a) Ovarian cancer is present?
b) Male breast cancer is present?

Answer 10

BRCA 1 and 2
tp53
PALB2
PTEN

Ovarian cancer: more likely BRCA 1

Male breast cancer: more likely BRCA 2

Question 11

Describe the genetic basis of familial breast cancer. (2)

Answer 11

1. Normal function of BRCA 1 and 2 is homologous recombination of double strand breaks
   a. Therefore mutations inhibit normal DNA repair
2. Mutations can be anywhere on the gene, or whole gene may be lost

Question 12

List 4 preventative measures for familial breast cancer.

Answer 12

Frequent breast exams
Regular screening (mammography/MRI)
Prophylactic mastectomy
Prophylactic oophorectomy/ salpingectomy

Question 13

List 7 gene mutations that may be involved in hereditary ovarian cancer.

Answer 13

Common:

• BRCA 1 and 2
• MLH1
• MSH2

Rare:

• RAD51C
• PTEN
• STKII
• PTCH

Question 14

What are the 3 types of hereditary colon cancer?

Answer 14

Hereditary non-polyposis colon cancer (HNPCC)
Familial adenomatous polyposis (FAP)
MYH polyposis

Question 15

List 4 genes which are involved in HNPCC.

Which are the most common ones?

Answer 15

MLH1 (50%)
MSH2 (40%)
MSH6
PMS2

Question 16

List 3 other types of cancer which are frequently associated with HNPCC.

Answer 16

Endometrial cancer
Stomach cancer
Ovarian cancer

Question 17

What sort of inheritance is involved in:

a) HNPCC?
b) FAP?
c) MYH polyposis?

Answer 17

HNPCC: autosomal dominant

FAP: autosomal dominant

MYH polyposis: autosomal recessive

Question 18

List 1 gene which is involved in familial adenomatous polyposis.

Answer 18

APC

NOTE: testing for children is recommended

Question 19

Describe the clinical features of familial adenomatous polyposis.

Answer 19

1. 100+ polyps are present

2. Associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE)

Question 20

Describe the clinical features of MYH polyposis. (1)

Answer 20

1. 15-200 polyps present

Question 21

Describe the genetic basis of cancer in:

a) HNPCC.
b) MYH polyposis.

Answer 21

HNPCC:

1. Mutation in a mismatch repair (MMR) gene causes inaccurate DNA replication
   a. This causes a high lifetime risk of colon cancer

MYH POLYPOSIS:

1. Mutation in MYH, a base excision repair (BER) gene which normally carries out DNA repair via glycosylase
   a. This results in insufficient DNA repair

Question 22

Discuss the genetic aspects of Li Fraumeni syndrome. Consider:

a) Type of inheritance.
b) Causes of Li Fraumeni.
c) Types of cancer associated with Li Fraumeni.
d) Risk of cancer in patients with Li Fraumeni.

Answer 22

Inheritance: autosomal dominant

Caused by: mutation in tp53

Types of cancer associated with Li Fraumeni syndrome:

1. Breast cancer
2. Brain tumours
3. Sarcoma
4. Leukaemia
5. Adrenocortical carcinoma

Risk of cancer in people with Li Fraumeni syndrome:
50% by 30 yo
90% by 50 yo

Question 23

Which types of DNA repair are commonly affected in hereditary cancer? (3)

State which genes and which type of cancer is most often associated with each one.

Answer 23

Homologous recombination of double strand breaks (BRCA 1 and 2)
-Causes breast/ovarian cancer

Mismatch repair genes (MLH1 and MSH6)
-Causes HNPCC

Base excision repair genes (MYH)
-Causes MYH polyposis