43.3 Genetic Basis of Malignancy

Question 1

What are viral oncogenes?

Answer 1

cancer-inducing genes within oncogenic viruses

Question 2

What are cellular proto-oncogenes?

Answer 2

Genes with normal roles in the regulation of cell growth, death or differentiation, but which contribute to malignancy as oncogenes when mutated, or inappropriately over-expressed.
*often GoF

Question 3

What do oncogenes predispose the cell to?

Answer 3

Dysregulated proliferation –> malignancy/ tumorigenesis

Question 4

What do oncogenes mostly encode?

Answer 4

• Transcription factors
• Factors in pro-growth signalling pathways (like mitogens and their receptors)
• Factors that enhance cell survival

Question 5

What are proto-oncogenes?

Answer 5

NORMAL genes that can be mutated or overexpressed, then become oncogenes

Question 6

Due to the single cell of origin, tumours are known as…

Answer 6

monoclonal

Question 7

Since tumours are so rare, which events increases the likelihood of them forming?

Answer 7

• Predisposing events like UV radiation and smoking - increased mutation frequency
• A cell with a single mutation surviving, creating a cell lineage that acquires further mutations
• Accumulation over time of several independent mutations

Question 8

Why are tumours rare?

Answer 8

• Mutations are rare - occur in 1 out of 106 mitotic cycles
• There are many repair mechanisms incl. 3’-5’ proofreading
• If mutations still persist - apoptotic and regulatory systems usually cause cell death

Question 9

What is the evidence for the thought that usually many mutations occur before cells become cancerous?

Answer 9

The incidence rates for cancer overall climb as age increases
More time to accumulate mutations
*requirement for the accumulation of several independent genetic events.

Question 10

What are the main types of carcinogens?

Answer 10

• Physical
• Chemical

Question 11

What are examples of physical carcinogens?

Answer 11

UV and ionising radiation

Question 12

What are examples of chemical carcinogens?

Answer 12

• Asbestos
• Tobacco smoke
• Alcohol
• Arsenic

Question 13

How does malignancy develop?

Answer 13

Through cells in the body accumulating changes to their genes. E.g. activation of oncogenes, and loss of tumour suppressor genes.

Question 14

What are the 2 different theories surrounding tumour heterogeneity?

Answer 14

Clonal evolution and cancer stem cell theory

Question 15

What is the clonal evolution theory?

Answer 15

*Peter Nowell (1976) → tumours arise from single mutated cell –clonal expansion→ form clones –genetic instability→ accumulation of additional stochastic mutations as tumour progresses → (epi)genetic changes gives rise to distinct subpopulations.
*Heterogeneity allows for selection of subclones/populations w/ accumulated driver mutations
- Hence evolutionary advantage.

Question 16

What is the cancer stem cell theory?

Answer 16

*Only CSCs (small subset of tumour cells that can self-renew + differentiate into non-tumorigenic progeny) are tumorigenic.
- I.e. can initiate + maintain tumour growth.
*Suggested heterogeneity develops over time as CSCs divide + differentiate asymmetrically → different tumour cell types w/ different phenotypes.
- Hence CSCs are source of heterogeneity

Question 17

How can loss of heterozygosity occur?

Answer 17

1. Chromosomal deletions or breaks that delete the tumour suppressor gene
2. Somatic recombination during mitosis where the normal gene copy is replaced with a mutant copy - daughter cells have LOH

Question 18

Since tumours are so rare, which events increases the likelihood of them forming?

Answer 18

• Predisposing events like UV radiation and smoking - increased mutation frequency
• A cell with a single mutation surviving, creating a cell lineage that acquires further mutations
• Accumulation over time of several independent mutations

Question 19

What is an important area of research that has confirmed the importance of cancer genes and led to new identifications?

Answer 19

Cancer genome projects, using high-throughput gene sequencing

Question 20

What is the role of tumour suppressor genes?

Answer 20

Encode proteins which suppress inappropriate cell cycle progression e.g. when DNA damage is present, by initiating cell cycle arrest, DNA repair, and apoptosis accordingly

Question 21

What is the 2-hit hypothesis?

Answer 21

Knudson’s 2-hit hypothesis (1950s) → study of familial bilateral retinoblastoma.
Found degree of inheritance. Contrasted to unilateral retinoblastoma which didn’t show heritability.
Led Knudson to propose 2 hit hypothesis (AR inheritance):
1st hit = inherited mutation in TSG
2nd hit = somatic loss of heterozygosity.
Carriers predisposed to much ↑er lifetime risk.

Question 22

What is the range of proteins that tumour suppressor genes encode?

Answer 22

*Gatekeeper genes
*Caretaker genes
*Landscaper genes

Question 23

What are gatekeeper genes?

Answer 23

*Gatekeeper genes → direct regulation of cell growth.
*Through inhibition of cell cycle progression/ inducing apoptosis
*RB1 (gatekeeper) mutation
- Found in familial (bilateral) retinoblastoma + diverse variety of sporadic cancers.

Question 24

What are caretaker genes?

Answer 24

maintain genome stability. If affected, allow mutations to accumulate.

Question 25

What are landscaper genes?

Answer 25

contribute to surrounding microenvironment.

Question 26

Are tumour suppressor genes dominant or recessive?

Answer 26

Recessive

Question 27

What are the consequences of mutation or absence of tumour suppressor genes?

Answer 27

Loss of cell cycle control - more proliferation, less DNA repair, etc

Question 28

Describe the evidence for the recessive nature of tumour suppressor genes (fusion experiments)

Answer 28

• Cells of normal and tumour phenotype were cultured together in a dish, then made to fuse
• Normal + tumour hybrid cells could not form tumours when injected into animals
• So malignant cell phenotype was recessive to wild-type growth phenotype

Question 29

What is loss of heterozygosity?

Answer 29

The inactivation of the functional second copy of a tumour suppressor gene

Question 30

Give examples of common TSGs.

Answer 30

*TP53 (TF capable of promoting cell cycle arrest/ apoptosis/ differentiation. activated by stresses)
- LoF –> continued cell cycle progression w/ unrepaired DNA damage, loss of R-point control.
*BRCA 1/2 –> encodes DNA repair proteins
- impaired ds break repair + mutagenesis → ↑ lifetime risk of breast/ ovarian cancer

Question 31

Give some examples of oncogenic genes.

Answer 31

*RAS
- KRAS Encodes K-ras involved in upstream MAPK signalling
- Missense mutation locks K-ras in GTP-bound state
*Philadelphia chromosomal translocation

Question 32

What is the Philadelphia chromosomal translocation?

Answer 32

Reciprocal translocation between ch 9 + 22 → in-frame fusion of BCR + ABL 1 → chimeric fusion oncogene BCR-ABL1
Deregulated tyrosine kinase activity → uncontrolled mitosis + genomic instability + inhibition of normal differentiation
Associated w/ CML (Chronic myeloid leukaemia)

Question 33

What can the GoF mutations in oncogenes lead to?

Answer 33

constitutive activation of proteins involved in proliferative signalling.
*missense mutations → hyperactive gene product
*↑ transcription
*Gene amplification → extra proto-oncogene copies