Neoplasia III

Question 1

4 groups for cancer?

Answer 1

Turn up genes that promote growth - oncogenes

Turn off genes that slow growth - tumour suppressor genes

Stop cell death - evasion of apoptosis

Break the spell checker - allows accumulation of spelling mistakes in oncogenes, tumour suppressors and those that evade apoptoses (permits progression through cell cycle even with mistakes)

Question 2

Describe the first mutation in cancer development

Answer 2

Should be one of the 4 groups. usually an oncogene, tumour suppressor, DNA repair or evasion of apoptosis

Question 3

Describe further mutations

Answer 3

Need more than 1 mutations for cells to proliferate; more mutations = increased growth , eventually leading to a self-sustaining growth (cancer)

Question 4

Stepwise progression in different cancers?

Answer 4

Some steps are important first steps and are often predictable in certain tumour types:
APC mutation in sporadic colon cancer

Question 5

Steps in cancer development?

Answer 5

Initiation - 1st mutation acquired
Promotion - further accumulation of mutations lead to increased growth and often results in pre-malignant phase (DYSPLASIA)
Persistence - mutations allow cell to grown in autonomously and there is unregulated abnormal growth; cells also have ability to invade connective tissue and blood vessels (MALIGNANCY)

Question 6

Stepwise progression of colon cancer?

Answer 6

Reasonably predictable steps:
Initiation - APC mutation
Promotion - KRAS
Persistence

Question 7

Describe oncogenes in cancer

Answer 7

Cells receive growth promoting signals - physiological

Signalling pathway is frequently altered in cancer and cells receive uncontrolled growth signals

Question 8

3 categories of growth receptors?

Answer 8

1. Receptors with intrinsic tyrosine kinase activity
2. 7 transmembrane G-protein coupled receptors
3. Receptors without intrinsic tyrosine kinase activity

Question 9

Describe the MAPK/ERK pathway

Answer 9

Normal MAPK/ERK pathway - EGF (Epidermal Growth Factor) binds to the receptor (EGFR) and begins a reaction involving RAS, RAF and other molecules and eventually MYC, which promotes transcription

In cancer - there can be (all steps are often mutated in cancer):
EGFR over expression (>50% adenocarcinomas) - many tumours have this mutation
RAS mutation
BRAF mutation - one of three RAF proteins found in mammals

Question 10

Action of herceptin?

Answer 10

Targets EGFR

Question 11

Drugs targeting EGFR?

Answer 11

Trastuzamab (Herceptin)
Erlotinib
Cetuximab

No point targeting EGFR if mutations further downstream

Question 12

Drugs targeting RAF?

Answer 12

Sarafenib

Geldanamycin

Question 13

Drugs targeting MEK?

Answer 13

Trametinib

Refametinib

Question 14

What is C-KIT?

Answer 14

Receptor tyrosine kinase that is mutated in GI stromal tumours (GIST) and leukaemias

Imatinib is a common therapeutic agent

Question 15

Describe RAS proteins

Answer 15

KRAS, HRAS and NRAS
All GTP-binding

Mutated in colon, lung, pacreatic, kidney, renal cancers and in melanoma

Inhibitors are licensed for use in melanoma

Question 16

Describe BRAF protein

Answer 16

Downstream of both receptor and RAS
50% of melanomas have RAF mutations
Some colonic malignancies involve RAF mutations, not APC

Inhibitors are licensed for melanoma treatment - Vemurafanib

Question 17

What is MYC?

Answer 17

One of the last points in the sequence - it is a NUCLEAR TRANSCRIPTION FACTOR that promotes growth, DNA replication, etc

Mutated commonly in lymphoma, neuroblastoma, small cell carcinoma of lung

Question 18

Describe the MYC gene in Burkitt’s lymphoma

Answer 18

MYC gene is broken apart (abnormal)

MYC translocation is diagnostic in Burkitt’s lymphoma

Question 19

Most commonly mutated kinase in cancer?

Answer 19

PI3K - mutations lead to:
Increased protein synthesis and cell growth
Cell cycle progression/proliferation
Survival/decreased apoptosis

Question 20

Treatment for PI3K mutations?

Answer 20

Limited success intrials
Targeted at haematological malignancies, e.g: chronic lymphocytic leukaemia
May be used in combo with receptor inhibitors

Question 21

Describe normal 7 transmembrane G proteins

Answer 21

G-protein coupled receptors are responsible for a wide range of physiological response and are often targets of pharmacological agents

Question 22

Describe the normal canonical Wnt pathway?

Answer 22

bind to G-protein coupled receptor (7 transmembrane proteins)
Activates other molecules like APC and β-catenin (promotes transcription

Question 23

Mutations in canonical Wnt pathway?

Answer 23

APC mutation - one of the earliest mutations in colorectal cancer and can occur as a germline mutation, causing an inherited condition (Familial Adenomatous Polyposis and Gardner’s syndrome)

β-catenin mutation - in ovarian cancer, endometrial cancer and in sarcomas

Question 24

PTCH mutations?

Answer 24

In skin cancers - basal cell carcinoma
Gorlin's syndorme
Odontogenic cysts (in jaw) and BCCs (Basal Cell Carcinomas)

Question 25

Describe non-intrinsic TK receptors?

Answer 25

Cannot auto-phosphorylate - recruit something else to do it for them

Question 26

JAK2 mutations?

Answer 26

In haematological malignancies - few therapeutic options

Question 27

What are tumour suppressor genes?

Answer 27

Encode proteins that inhibit the cell cycle and are often pre-fixed by a “p”, e.g: p53

Question 28

Describe p53 in cancer

Answer 28

Most commonly mutated protein across all cancers and has various roles in the cell cycle

Question 29

Functions of p53

Answer 29

Cell cycle arrest - senses DNA abnormalities at G1 and pauses cell cycle
Increases levels of p21, which is a CDK inhibitor, thus inhibiting cell cycle (CDK is activated by cyclins)

Induces apoptosis - if DNA is repaired, p52 restarts the cell cycle. If repair is not possible, p53 initiates apoptosis (via BAX apoptosis)

Question 30

What is Von-Hippel Lindau (VHL)?

Answer 30

Can be syndrome - increases risk of renal cancers

Loss of VHL increases levels of angiogenic growth factors

Question 31

What is PTEN?

Answer 31

Increases transcription of p27 - blocks CDKs and cell cycle progression
Inhibits PI3K/AKT pathway

Without PTEN, and so p27, cells can proliferate in an uncontrolled fashion

Question 32

Types of DNA repair genes?

Answer 32

DNA is constantly damaged and constantly repaired

Mismatch repair genes
MLH1, MLH2, PMS1, PMS2 - associated with HNPCC (Hereditary Non-Polyposis Coli) and Muir Torres (sub-type of HNPCC)

Question 33

Finding spelling mistakes?

Answer 33

Can look at micro-sattellite instability (impaired DNA mismatch repair) - regions where it is easy to identify spelling mistakes that should not be there

Question 34

BRCA mutations?

Answer 34

BRCA1 and BRCA2 mutations in breast cancer

Also, an increased risk of ovarian and pancreatic cancers

Question 35

Function of BRCA?

Answer 35

Involved in oestrogen and androgen receptor regulation

Involved in DNA repair and cell cycle arrest at G1/S phase

Question 36

How do cancer cells evade apoptosis?

Answer 36

p53 increases BAX levels
BAX stops BCL2
BCL2 is anti-apoptotic

Tumour cells often switch on BCL2 (cannot have apoptosis with this on) and switch off BAX

Question 37

Physiological apoptosis?

Answer 37

Normal lymph nodes need apoptosis to get rid of “self-reactive” lymphocytes

In normal follicles, BCL2 is witched off

Question 38

Examples of cancers that avoid apoptosis?

Answer 38

Lots of lymphomas - inc. follicular lymphoma (tumour of cells within follicles)
Switch on BCL2 on chromosome 18 (IgH turns on BCL2)