L21- Carcinogenesis: molecular hallmarks of cancer cells

Question 1

What do Caretaker genes do:

Answer 1

maintain genetic stability by repairing damaged DNA and replication errors

If these get mutated — > Genetic instability is a common feature of most tumour cells

Question 2

What are gatekeeper genes?

Answer 2

• play important roles in regulating normal growth:
• Negative regulators of the cell cycle and proliferation
• Positive regulators of apoptosis
• Positive regulators of cell differentiation

Question 3

What do Carcinogens do to TSGs?

Answer 3

Carcinogens induce molecular abnormalities in TSGs

cause reduced/lack of protein expression or inactivation of protein – LOSS OF FUNCTION

Question 4

What gene is affected in Retinoblastoma?

Answer 4

Gene: RB1

Gatekeeper

Question 5

What gene is affected in Li-Fraumeni?

Answer 5

p53

gatekeeper/caretaker

Question 6

What gene is affected in Familial adenomatous polyposis?

Answer 6

APC

Gatekeeper

Question 7

What gene is affected in Familial breast cancer?

Answer 7

BRCA1, BRCA2

Caretaker

Question 8

What gene is affected in Hereditary non-polyposis colorectal cancer?

Answer 8

hMLH1, hMSH2

Caretaker

Question 9

What are Proto-oncogenes ?

Answer 9

promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis

Question 10

What are Oncogenes?

Answer 10

mutations lead to activated versions or increased expression of proto-oncogenes – GAIN OF FUNCTION

—> inc levels of proliferation, survival, angiogenesis and inhibition of apoptosis

Only 1 copy of the gene needs to be activated to induce a gain of function

Question 11

Mechanisms of oncogene activation : Translocation

Answer 11

Translocation of a proto-oncogene from a low transcriptionally active site to an active site

Question 12

Mechanisms of oncogene activation: Point mutation

Answer 12

substitution of a single base pair can alter an amino acid in the protein causing it to become hyperactive

Question 13

Mechanisms of oncogene activation: Amplification

Answer 13

by insertion of multiple copies of an oncogene – increased expression

Question 14

Multi-step tumorigenesis …briefly discuss steps leading to a neoplastic cell

Answer 14

activation of oncogenes

inactivation of TSGs

Minimum of 3 genetic alterations are needed to transform a normal cell into a neoplastic cell

Question 15

Do tumour cells need the presence of positive growth factors before dividing?

Answer 15

Tumour cells acquire the ability to grow in the absence of these factors

Tumour cells are also unable to respond to negative growth factors

Question 16

What is the role of the RB (Retinoblastoma protein) gene

Answer 16

key regulator of cell cycle by preventing progression from G1 to S phase

-ve GFs inhibit progression of cell cycle by activating Rb protein

Question 17

What happens to the telomeres of Tumour cell’s DNA?

Answer 17

Tumour cells express telomerase that replaces the lost material and cells become immortal

Question 18

Function of p53

Answer 18

P53 induces cell cycle arrest to allow repair of DNA damage

But also induces apoptosis if too much damage

TP53 inactivation leading to loss of apoptotic response is the most common genetic abnormality in human tumours —> Li-Fraumeni

Question 19

What is angiogenesis?

Answer 19

Generation of new blood channels

vascular endothelial growth factor (VEGF) – an angiogenic factor plays an important role

Question 20

Why do Invasion and metastasis occur?

Answer 20

Many tumours show loss of E-cadherin through mutation/hypermethylation of the gene (epithelial cells are held tightly by this)

Results in epithelial-mesenchymal transition (EMT)

Mesenchymal cells are motile and secrete proteases - allows them to break through basement membrane and invade the underlying stroma

Question 21

What are clinical applications of tumour markers?

Answer 21

Screening

• Detection of tumour
• Detection of predisposition

Diagnosis
-Identification of type and sub-type

Prognosis
-Certain mutations confer worse survival

Therapy

• Predictive markers for therapeutic response
• Development of targeted drugs or gene therapies

Monitoring

• Response to treatment
• Detecting relapse

Question 22

The Prostate-specific antigen (PSA) marker is useful to diagnose…?

Answer 22

prostate cancer

Question 23

The CA125 serum antigen is a marker useful to diagnose?

Answer 23

ovarian cancer

Question 24

Predictive markers for therapeutic response : HER2

Answer 24

codes for a +ve growth factor receptor

Overexpression found in ~30% of breast tumours (gene amplification)

Herceptin is an antibody drug targeted to HER2 and dampens the effects of an overactive HER2 receptor

Only patients with HER2 overexpression have Herceptin treatment as individuals without overactive HER2 receptors will have no beneficial effect