Cancer genetics

What is cancer?

A disease of multicellular organisms characterised by uncontrolled cell division.
Second leading cause of death worldwide.

What proportion of cancers have an inherited predisposition?

~10% of cancers show inherited susceptibility.

What proportion of human cancers are linked to environmental carcinogens?

~80% are related to exposure to carcinogens (environmental agents).

Are cancers clonal or polyclonal?

Clonal — most cancers originate from a single transformed cell.

What two categories of genes are most commonly mutated in cancer?

• Oncogenes (gain-of-function)

• Tumour suppressor genes (loss-of-function)

What is an oncogene?

A mutated proto-oncogene that is overactive and promotes cancer growth.

What is a proto-oncogene?

A normal cellular gene involved in growth/division that can become an oncogene if mutated.

What type of mutation creates an oncogene?

Gain-of-function mutation.

What is a tumour suppressor gene?

A gene that prevents uncontrolled cell division; cancer occurs when it is inactivated.

What type of mutation affects tumour suppressor genes?

Loss-of-function mutation.

List the four main ways proto-oncogenes become oncogenes.

• Missense mutation

• Gene amplification

• Chromosomal translocation

• Viral integration

Which oncogene family is commonly activated by missense mutations?

RAS genes (H-ras, N-ras, K-ras).

How does a missense mutation activate RAS?

Alters amino acid sequence → protein becomes constitutively active (always “on”).

What is gene amplification?

Increase in copy number of an oncogene → increased protein expression.

Give examples of oncogenes activated by amplification.

• c-MYC (leukaemia)

• N-MYC (neuroblastoma)

• ERBB2 / HER2 (breast cancer)

What are the three major consequences of chromosomal translocations in cancer?

• Activation of proto-oncogenes (juxtaposition to Ig/TCR loci)

• Formation of fusion genes

• Position effects (ectopic expression)

Why do Ig or TCR loci activate oncogenes?

They contain strong enhancers/promoters → abnormal oncogene expression.

Which oncogene is activated in Burkitt lymphoma?

MYC, commonly via t(8;14) translocation.

What is the Philadelphia chromosome?

t(9;22) translocation producing BCR-ABL fusion protein.

Why is BCR-ABL oncogenic?

It encodes a constitutively active tyrosine kinase → uncontrolled cell proliferation.

What targeted therapy treats BCR-ABL–positive CML?

Imatinib (Gleevec) — inhibits ABL kinase activity.

What is promoter hijacking?

Oncogene activation by misplacement of a strong promoter near a proto-oncogene.

Give an example of promoter hijacking.

TMPRSS2–ERG fusion in prostate cancer.

What is enhancer hijacking?

Relocation of an enhancer to activate an oncogene abnormally.

How can viruses cause cancer?

By integrating into host DNA and activating proto-oncogenes.

Which virus carries the src oncogene?

Rous sarcoma virus (RSV).

. Roughly what percentage of human cancers are virus-associated?

~15%.

What is the classic tumour suppressor gene model?

Knudson’s two-hit hypothesis.

What does the two-hit model state?

Both alleles of a tumour suppressor gene must be inactivated for cancer to develop.

Which disease demonstrated the two-hit hypothesis?

Retinoblastoma (RB gene).

Why does inherited retinoblastoma occur earlier in life?

One mutation is already present → only one additional hit needed.

What is genome maintenance?

Mechanisms that detect DNA damage and prevent damaged cells from dividing.

What are checkpoint proteins?

Proteins that halt the cell cycle if DNA damage is detected.

How do DNA repair defects promote cancer?

Allow accumulation of mutations → oncogene activation or tumour suppressor loss.

Which DNA repair disorder predisposes to skin cancer?

Xeroderma pigmentosum (defective nucleotide excision repair).

How can tumour suppressor genes be silenced without mutation?

Epigenetic changes (e.g. DNA hypermethylation).

What is DNA hypermethylation associated with in cancer?

Silencing of tumour suppressor genes.

How can histone modifications contribute to cancer?

By increasing oncogene expression or decreasing tumour suppressor expression.

Can epigenetic changes be targeted therapeutically?

Yes — DNA methyltransferase inhibitors and histone-modifying drugs are used (e.g. leukemia).