L9 oncogenes and tumour suppressor genes

Question 1

normal cells

Answer 1

socially responsible for the survival of the whole organism

divide, move, differentiate and die when appropriate

Question 2

cancer cells

Answer 2

selfish

accumulate mutations, divide uncontrollably and move throughout the body at the expense of neighbouring cells and the whole organism

Question 3

cancer is caused by genetic (or epigenetic changes)

Answer 3

caused by genetic changes that affect gene expression/function

genetic changes caused by:

1. mutations
2. chromosomal abnormalities
3. introduction of genes by viruses

Question 4

Categories of cancer

Answer 4

see onenote

1. carcinoma
2. sarcoma
3. melanoma
4. leukemia
5. lymphoma
6. retinoblastoma, glioblastoma, medulloblastoma, neuroblastoma

Question 5

cancer

Answer 5

disease featuring abnormal and improperly controlled cell division resulting in invasive growths, tumours that may spread throughout the body

strongly related to age

long exposure to mutagens increases incidence

Question 6

benign vs malignant tumours

Answer 6

benign

• non cancerous
• generally stop growing, do not spread to other parts of the body and do not create new tumours

malignant

• cancerous
• can invade healthy tissues, interfere with body functions, can draw in blood vessels to get nutrients and oxygen for more growth
• can spread to other parts of the body and create new tumours

Question 7

Hallmarks of cancer

Answer 7

1. sustaining proliferative signalling
2. evading growth suppressors
3. activating invasion and metastasis
4. enabling replicative immortality
5. inducing angiogensis
6. resisting cell death

Question 8

Tumorigenesis

Answer 8

1. resisting cell death
2. sustaining proliferative signalling
3. evading growth suppressors

Question 9

Metastasis

Answer 9

the spread of cancer cells from one site in the body to another site

Tubes throughout your body, if tumour can get into transport system, can get throughout your body

1. inducing angiogenesis
2. activating invasion and metastasis

Question 10

Tumour development

Answer 10

see onenote diagram

cancer occurs by cells acquiring multiple mutations over a long period of time that gradually transform them into cancer cells

Question 11

Tumorigenesis is a balance between proliferation and cell death

Answer 11

increase proliferation/decrease apoptosis => tumour

apoptosis: programmed cell death

cell proliferation: increase in cell number by division

senescence: cell which is still alive but not actively dividing, in a state of arrest which is normally irreversible

Question 12

Oncogene

Answer 12

see onenote

a gene that, when mutated/expressed at high levels helps turn a normal cell into a cancer cell (transformation)

normal form - proto-oncogene, involves in cel proliferation, growth, invasiveness e.g. Ras, PI3K, twist

Question 13

Tumour suppressor gene

Answer 13

see onenote

a gene that acts to prevent a normal cell from turning into a cancer cell

• limit cell proliferation, promoting cell death, preventing metastasis
• knudson two hit theory
• anti-oncogenes
• p53, pten, Rb

Question 14

Normal cellular roles of proto-oncogenes and tumour suppressor genes

Answer 14

see onenote

Question 15

oncogenes vs tumour suppressor genes

Answer 15

see onenote

Question 16

Possible ways by which proto-oncogenes can be activated

Answer 16

see onenote

Question 17

Knudson “two hit” model for the inactivation of tumour suppressor genes

Answer 17

see onenote slides

Knudson “two-hit” model

• One copy knocked down, wait for the other copy to be knocked out => loss of function
• Loss of first copy could be random or inherited

Loss of second copy - loss of heterozygosity

Question 18

Inactivation of tumour suppressor genes can involve both genetic/epigenetic changes

Answer 18

see onenote

Question 19

sequencing of many cancers reveal different pattern of mutations in oncogenes vs TSGs

Answer 19

see onenote

Can tell if its oncogene or tumour suppressor from looking at amount and spread of mutations

TSGs most mutations are truncating

oncogenes mutations found repeatedly at key aa positions, truncating mutations are rare

Question 20

Burkitt’s lymphoma

Answer 20

see onenote slides

aggressive cancer of the lymphatic system involving over proliferation of B lymphocytes

protooncogenic translocation to a region of high transcriptional activity

• reciprocal translocation between chromosome 8 and 14
• Myc protooncogene gets put next to powerful enhancer => expressed at high level, drive cell growth and proliferation pathway at high levels

Question 21

Increased myc expression causes cell proliferation

Answer 21

see onenote

Myc is a TF, promotes cell growth and proliferation by controlling expression of target genes in response to many signalling pathways

excessive myc => hyper-proliferation of lymphocytes

Question 22

Chronic myeloid leukaemia (CML)

Answer 22

cancer in which the bone produces too many granulocytes (a type of white blood cell)

• reduced number of healthy white blood cells, RBC and platelets
• leads to increased infection, anaemia and easy bleeding

Question 23

Possible ways proto-oncogene can be activated - gene fusion event creating an altered function protein

Answer 23

see onenote

Question 24

CML caused by reciprocal chromosomal translocation

Answer 24

see onenote

reciprocal translation between chromosomes 9 and 22
- results in philadelphia chromosome and a fusion between c-abl gene which encodes kinase and Bcr genes => increases kinase activity

Question 25

Bcr-Abl oncogene is constitutively active

Answer 25

see onenote

constitutively active kinase => misregulation of cellular signalling pathway that it mediates

Question 26

Retinoblastoma (Rb)

Answer 26

regulates the cell cycle

rare childhood tumour which develops from neural progenitor cells in the immature retina

Question 27

Rb protein inhibits the cell cycle

Answer 27

see onenote slides

Without Rb, E2F is costanlty turned on

Question 28

p53

Answer 28

see onenote

tumour suppressor, “guardian of the genome”

homozygous loss of p53 found in many carcinomas

Almost every cancer has lost p53 function

P53 turns on most anti-cancer mechanisms

Question 29

Li-Fraumeni syndrome (LFS)

Answer 29

cancer predisposition syndrome where the molecular basis is a loss of function germline mutation in the p53 gene

inheriting 1 faulty copy of p53 increases risk of cancer and lowers median age at diagnosis