Cancer Genetics

Question 1

What is cancer?

Answer 1

All cancers derive from single cells that have changes in their genetic sequences of key genes know as cancer genes

Therefore they are genetic diseases

Uncontrolled cell replication

Question 2

What causes cancer?

Answer 2

Environmental factors - eg chemicals and radiation such as smoking and UV

Exogenous factors - viruses

Genetic factors - hereditary

Multi factoral

Question 3

What are benign tumours?

Answer 3

Mass of well differentiated cells that grow slowly

Lack ability to invade neighbouring cells

Question 4

What are malignant tumours?

Answer 4

Not self limited in its growth (escapes apoptosis and can produce new blood vessels)

Poorly differentiated

Can metastasise

Question 5

What does the microscope appearance of cancer cells look like?

Answer 5

Can be larger or smaller than normal

Large and possibly irregular nucleus

Disorganised

Question 6

What are some types of cancer?

Answer 6

Carcinoma - epithelial (breast, lung, colon)

Sarcoma - connective tissue (bone cartilage fat and muscle)

Lymphoma - cancers of the immune system and lymph nodes

Leukaemia - cancers of immature blood cells

Question 7

What is the most common cause of cancer deaths?

Answer 7

Lung cancer

Then bowel, breast and prostate

Question 8

What are the six hallmarks of cancer?

Answer 8

Self sufficiency in growth signals

Insensitivity to growth signals

Tissue evasion and metastasis

Limitless replicative potential

Sustained angiogenesis

Evading apoptosis

(Genome instability and avoiding immune destruction have also been added)

Question 9

What are germline mutations?

Answer 9

Occur in the sperm or the egg

Are heritable and effect all cells of offspring

Very rare (10% of cancers)

Question 10

What are somatic mutations?

Answer 10

Occur in all other cells (not gametes)

Non heritable

Very common (90%)

Question 11

What do position cloning linkage studies identify?

Answer 11

Cancer germline mutations

Rare families with a predisposition to a certain cancer undergo linkage analysis

Their chromosomes are mapped and cloned.

The chromosome region where the mutation is though to be is located

These can be sequenced and compared against members of the normal population

Eg BRCA-1 causing breast cancer

Question 12

What are the different types of mutation?

Answer 12

Single base substitutions - silent, nonsense or missense

Deletions

Insertions

Duplications

Inversions

Translocations

Often leads to chromasomal instability or aneuploidy

Question 13

What are the stages of carcinogenesis?

Answer 13

Initiation

Promotion

Progression

Starts of with one mutation in a tumour surpressor gene (germline or somatic). This is followed by mutations in other genes which leads to full cancer

Question 14

Some cancers have distinct somatic mutations, what is an examle of this?

Answer 14

Mutations signature to UV light involve a C to T transition in dipyrimide context

If these DNA changes occur in critical genes such as BRAF a kinase, this can lead to inappropriate cell growth and cause malignant melanoma

Question 15

What distinct somatic mutation is characteristic of some lung cancer?

Answer 15

G to T transition

Present in 30% of smokers lung cancer

But only 12% of non smokers

Question 16

What are driver and passenger mutations?

Answer 16

Passenger mutatations -many can be tolerated by somatic cells. No growth advantage

Driver mutations - few mutations can confer a selective advantage and are recurrently found
(Cancer genes are an example of these)
Driver mutations cause clonal expansion

When a passenger mutation occurs on the same gene as a driver mutation: hitch hiking

Question 17

How might passenger and driver mutations differentiated?

Answer 17

If mutations are found more commonly in cancer cells than would be expected due to normal mutation rated it might be a driver gene

However it is very hard to accurately estimate background mutational frequency

Driver mutations also have a larger influence on protein function than passenger mutations

Question 18

What is an oncogene?

Answer 18

A gene that has the potential to cause cancer

Often being as Proto oncogenes. These undergo a single mutation (dominant, gain of function) and are up regulated, predisposing the cell to cancer and becoming cancer genes

They can cause cells designated for apoptosis to survive and proliferate instead

Question 19

Most cancer causing mutations in oncogenes are acquired not inherited. How?

Answer 19

Generally oncogenes are activated by chromosome rearrangements, gene anmplification (Myc), or mutation (Ras)

Question 20

What are some oncogene mutations that result in rare familiar cancer?

Answer 20

RET - medullary cancer of thyroid

KIT - hereditary gastrointestinal stromal tumours

MET - hereditary papillary renal cancer

CDK4 - malignant melanoma

Question 21

What are tumour surpressor genes?

Answer 21

A gene that regulates a cell during cell division and replication

When it mutates it results in a loss of its function

Can potentially cause abnormal cell growth

Generally a recessive, loss of function mutation

Eg. BRCA-1 and BRCA-2

Question 22

What is the two hot hypothesis?

Answer 22

Eg applies to retinoblastama

Most loss of function mutations that happen in tumour surpressor genes are recessive. To cause cancer both genes in a cell must be mutated

In the first hit, one mutated gene is inherited into every cell of the body. However this does not cause cancer

The second hit is a somatic mutation in the other gene of the gene pair. This causes cancer

Bilateral cases are hereditary, uni lateral are not?