Genetic Aspects of Cancer Flashcards
What are the 4 properties needed for cells to become cancerous?
- Proliferative signalling
- Avoidance of apoptosis
- Bypassing replicative senescence
- Insensitivity to anti-growth signalling
What 3 types of gene are involved in hereditary cancer?
- Tumour suppressor genes
- Proto-oncogenes
- Stability/caretaker genes
Define “tumour suppressor genes”.
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
Define “proto-oncogenes”.
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
Define “stability/caretaker genes”.
A type of tumour suppressor gene which is involved in DNA repair
List the 3 types of tumour suppressor genes.
Give some examples of each.
Inhibiting cell cycle progression:
Rb gene
tp53 gene
NF1 gene
Promoting apoptosis:
tp53 gene
BAX gene
DNA repair:
90+ types of gene
How do the following types of genes cause cancer?
a) Tumour suppressor genes
b) Proto-oncogenes
c) Stability/caretaker genes
TSGs:
- Loss of function mutations make them switch off
- Both copies of the TSG gene must be lost
PROTO-ONCOGENES:
- Activation/gain of function mutations switch them on
- Only one copy needs to be lost
STABILITY GENES:
- Loss of function mutation
- Both copies of the stability gene must be lost
Outline Knudson’s two hit hypothesis.
Give 2 examples of inherited cancer which follows this theory.
- A mutation in one copy of a TSG is passed on via autosomal dominant inheritance
- A subsequent somatic mutation of the remaining normal gene is needed to cause cancer
EXAMPLES:
BRCA1 and 2
MEN1 (multiple endocrine neoplasia)
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.
FAMILY HISTORY:
- More than one affected individual in familiy
- Similar cancers present (e.g. breast and ovarian)
- Early onset
INDIVIDUAL:
- Multiple primary tumours
- Early onset
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?
BRCA 1 and 2
tp53
PALB2
PTEN
Ovarian cancer: more likely BRCA 1
Male breast cancer: more likely BRCA 2
Describe the genetic basis of familial breast cancer. (2)
- Normal function of BRCA 1 and 2 is homologous recombination of double strand breaks
a. Therefore mutations inhibit normal DNA repair - Mutations can be anywhere on the gene, or whole gene may be lost
List 4 preventative measures for familial breast cancer.
Frequent breast exams
Regular screening (mammography/MRI)
Prophylactic mastectomy
Prophylactic oophorectomy/ salpingectomy
List 7 gene mutations that may be involved in hereditary ovarian cancer.
Common:
- BRCA 1 and 2
- MLH1
- MSH2
Rare:
- RAD51C
- PTEN
- STKII
- PTCH
What are the 3 types of hereditary colon cancer?
Hereditary non-polyposis colon cancer (HNPCC)
Familial adenomatous polyposis (FAP)
MYH polyposis
List 4 genes which are involved in HNPCC.
Which are the most common ones?
MLH1 (50%)
MSH2 (40%)
MSH6
PMS2
List 3 other types of cancer which are frequently associated with HNPCC.
Endometrial cancer
Stomach cancer
Ovarian cancer
What sort of inheritance is involved in:
a) HNPCC?
b) FAP?
c) MYH polyposis?
HNPCC: autosomal dominant
FAP: autosomal dominant
MYH polyposis: autosomal recessive
List 1 gene which is involved in familial adenomatous polyposis.
APC
NOTE: testing for children is recommended
Describe the clinical features of familial adenomatous polyposis.
- 100+ polyps are present
2. Associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE)
Describe the clinical features of MYH polyposis. (1)
- 15-200 polyps present
Describe the genetic basis of cancer in:
a) HNPCC.
b) MYH polyposis.
HNPCC:
- Mutation in a mismatch repair (MMR) gene causes inaccurate DNA replication
a. This causes a high lifetime risk of colon cancer
MYH POLYPOSIS:
- Mutation in MYH, a base excision repair (BER) gene which normally carries out DNA repair via glycosylase
a. This results in insufficient DNA repair
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.
Inheritance: autosomal dominant
Caused by: mutation in tp53
Types of cancer associated with Li Fraumeni syndrome:
- Breast cancer
- Brain tumours
- Sarcoma
- Leukaemia
- Adrenocortical carcinoma
Risk of cancer in people with Li Fraumeni syndrome:
50% by 30 yo
90% by 50 yo
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.
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
