CA2: Clinical cancer genetics

Question 1

Give examples of inherited cancers and what are these

Answer 1

1. Retinoblastoma
2. Multiple endocrine tumours
3. Breast cancer
4. Colon cancer

These cancers are inherited because people carry rare germ line mutations which increase the risk of the cancer

Question 2

What is a pholadelphia chromosome

Answer 2

This is seen in chronic myelogenous leukemia (CML) where there is a translocation of pieces from chromosome 9 to 22 - this leads to uncontrolled cell proliferation

Question 3

What is a gatekeeper gene (tumour suppressor gene)

Answer 3

Regulates tumour growth by controlling proliferation or promoting cell death

Question 4

What is a caretaker gene (tumour suppressor gene)

Answer 4

DNA repair genes or genes protecting the genome from acquiring or retaining DNA damage

Question 5

How does inactivation of a gatekeeper gene lead to cancer

Answer 5

Increases risk because only 1 further mutation is needed to initiate neoplasia

Question 6

How does inactivation of a caretaker gene lead to cancer

Answer 6

Increases risk because only 3 more mutations are needed to initiate neoplasia and it will also increase the probability of all further mutations

Question 7

What are polymorphisms

Answer 7

Changes in DNA sequences that occur commonly in the population (these are not mutations)

Question 8

How does cancer develop

Answer 8

Through multiple mutations - the rate of mutation is constant but the risk of cancer increases with age : there are 3-6 rate limiting steps in the development of most cancers

Question 9

How are oncogenes formed and what are these

Answer 9

By mutation of the proto-oncogene or increased expression which produces oncoprotein - oncogenes have the potential to cause cancer

Question 10

How are growth factors involved in DNA synthesis and the production of cascades of oncogenes

Answer 10

The growth factor binds to the receptor

There is activation of oncogene and cascade of events

Transcription factor is activated

Cyclin d1 is transcribed

Cyclin-dependant-kinase 4 forms DNA

Question 11

What is the perturbation of EGF (epidermal growth factor) signalling in oral cancer

Answer 11

The increased amount of growth factor receptors on the cell surface in advances SCC in the oral cavity - this is due to an over-expressed proto-oncogene which amplifies DNA synthesis and the production of oncogene cascades

Question 12

Explain how MYC causes over expression of proto-oncogenes

Answer 12

This gene amplification is caused by chromosome rearrangement and is implicated in Burkitt’s lymphoma = when a chromosomal translocation moves an enhancer sequence within the vicinity of the MYC gene

MYC gene codes for transcription factors thus with the enhancer sequence moved, there is an increase in transcription factor production

Question 13

Explain how Philadelphia chromosome (BCR-ABL) causes disruption

Answer 13

BCR-ABL gene is found on the Philadelphia chromosome found in CML (due to translocation of chromosome 9 and 22)

BCR-ABL codes for receptor tyrosine kinase which is activated causing uncontrolled cell proliferation - genes are over expressed causing cancer

Question 14

What is the loss/reduced function of tumour suppressor genes associated with

Answer 14

Cancer

1. RB1 = Retinoblastoma and Osteosarcoma
2. APC = Colon cancer
3. CDKN2A/p16 INK4A = Melanoma
4. TP53 = Breast cancer
5. BRCA1 + BRCA2 = Breast and Ovarian cancer
6. MSH1 = Colon cancer

Question 15

What is the two-hit hypothesis for retinoblastoma

Answer 15

Hypothesis that most tumor suppressor genes require both alleles to be inactivated (through mutations/ epigenetic silencing) to cause a phenotypic change