Pathology 9 - Neoplasia 3

Question 1

What are the 4 cancer causing groups of genes?

Answer 1

Oncogenes - turn these up (cause mutation from photo-oncogene to oncogene)Tumour supressor genes - turn these offTurn off genes that stop cells dying = evasion of apoptosisBreak the spell checker genes = allows accumulation of spelling mistakes in oncogenes, tumour suppressors and those that avoid apoptosis (permits progression through the cell cycle even with mistakes)

Question 2

How does cancer develop?

Answer 2

You need 2 mutations in a gene for cancer to develop (2 hit hypothesis)Once you have the 2 hits the cells will begin to rapidly proliferate and will accumulate more and more mutations until they become a self sustaining growth *the 2 it hypothesis refers to tumour suppressor genes

Question 3

What are the 3 key stages in the development of cancer?

Answer 3

InitiationPromotionPersistence

Question 4

What is initiation?

Answer 4

The 1st mutation is acquired (often in one of the group of 4)

Question 5

What is promotion?

Answer 5

Further accumulation of mutationsAdditive effectIncreased growthOften results in a “pre-malignant” phase - dysplasia

Question 6

what is progression?

Answer 6

Cell has developed mutations that allow it to grow in na autonomous fashionUnregulated abnormal growthCells have the ability to invade connective tissue and blood vesselsMalignancy has now been achieved

Question 7

What are the 3 categories of growth factors?

Answer 7

Receptors with intrinsic tyrosine kinase activity7 transmembrane G protein-coupled receptorsReceptors without intrinsic tyrosine kinase activity

Question 8

What is the MAPK/ERK pathway?

Answer 8

a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell

Question 9

What lesions in the ERK-signalling pathway can cause cancer? (4)

Answer 9

ERGF over expression (most cancers)RAS mutation RAF mutationMyc mutation(we can use “personalised” drugs that specifically target these mutations)*these are all photo-oncogenes

Question 10

What tyrosine kinase receptors are sometimes mutated in gastrointestinal stromal tumours (GIST) and leukemias?What therapeutic agent is used to treat this?

Answer 10

C-KIT (growth receptor)Imatinib

Question 11

What is RAS?

Answer 11

RAS is a family of related proteins that are involved in transmitting signals within cellswhen switched on, RAS turns n other proteins, which ultimately turns on genes involved in cell growth, differentiation and survivalas a result, mutations in RAS can lead to the production of permissively active RAS proteins (GTP binding proteins)Proto-oncogene

Question 12

What type of cancers commonly have RAS mutations? (6)

Answer 12

ColonLungPancreaticBladderRenalMelanoma

Question 13

What is BRAF?

Answer 13

A downstream of receptor and RAF - it is a photo-oncogene involved in the ERK-signalling pathwayProto-oncogene

Question 14

What cancers are associated with (B)RAF?

Answer 14

Melanoma (50% are RAF mutated)Some colonic malignancies

Question 15

What is an inhibitor of BRAF that is licensed for melanoma treatment?

Answer 15

Vemurafanib

Question 16

What is Myc?

Answer 16

A nuclear transpiration factor that promotes growth - DNA replicationPro-oncogene

Question 17

What cancers are commonly affected by Myc mutation? (3)

Answer 17

LymphomaNeuroblastomaSmall cell carcinoma of the lungBurkitt lymphoma

Question 18

What is the most common mutated kinase receptor in cancer?

Answer 18

P13K

Question 19

What pathway is APC a part of?

Answer 19

Canonical Wnt Pathway

Question 20

Apart from APC, what other protein in the canonical WnT pathway can become mutated causing cancer?What cancers is this commonly mutated in?

Answer 20

Beta-cateninOvarian cancerEndometrial cancerSarcomas

Question 21

What does a mutation in JAK2 commonly occur in?

Answer 21

Haematological malignancies

Question 22

What type of proteins are often prefixed with “p”?

Answer 22

Tumour supressor genes

Question 23

What is the most commonly mutated protein across all cancers?

Answer 23

p53 - tumour supressor gene

Question 24

What does p53 do?

Answer 24

Senses DNA abnormalities at G1 and pauses the cell cycle - increases levels of p21 which is a CDK inhibitor If DNA is repaired, p53 restarts the cell cycleIf repair is not possible, p53 initiates apoptosis

Question 25

What is CDK activated by?

Answer 25

Cyclins

Question 26

What cycle does p53 initiate apoptosis by?

Answer 26

BAX cycle

Question 27

What Von-Hippel Lindau disease?

Answer 27

a disease which results from a mutation in the von Hippel–Lindau tumor suppressor gene which causes multiple tumours to develop (mostly renal cancers)- loss of a functioning VHL gene increases levels of angiogenic growth factors

Question 28

What does PTEN do?

Answer 28

Increased transcription of p27 - p27 blocks CDKs and cell cycle progression and therefore inhibits P13K/AKT pathwayTherefore a mutation in this causes proliferation in an uncontrolled manner

Question 29

What are 4 examples of DNA repair genes?

Answer 29

MLH1, MLH2, PMS1, PMS2 - mutations in these can lead to the likes of HNPCC and Muir Torres

Question 30

What parts of DNA do DNA repair genes specifically look at?

Answer 30

Microsatellite regions

Question 31

What type of genes is BRCA?

Answer 31

DNA repair genes/ tumour supressors

Question 32

What types of cancers do BRCA mutations increase your risk of?

Answer 32

BreastOvarianPancreatic

Question 33

What genes are involved in evasion of apoptosis and how?

Answer 33

p53 and BCL2 p53 increases levels of BAXBAX stops BCL2BCL2 is anti-apoptotic

Question 34

Is Bcl2 pro or anti-apoptotic?

Answer 34

Anti-apoptotic

Question 35

Is Bcl2 normally on or off in normal lymph node follicles?

Answer 35

Off - need apoptosis to get rid of self reactive lymphocytes

Question 36

How do many lymphoma cells avoid apoptosis?

Answer 36

By switching on BCL2