PHAR3922 - Cancer Genomics

What role does genetic variation play in the pathophysiology of cancer?

Genetic variation (somatic and germline mutations) alters cell cycle regulation, apoptosis, DNA repair, and proliferation pathways. These mutations cause tumour development, clonal diversity, and acquisition of cancer hallmarks.

What proportion of tumour development is due to somatic vs germline mutations?

Somatic mutations: ~90% (spontaneous)

Germline mutations: ~20% (inherited at birth);

Both: ~10%.

What is clonal diversity in cancer cells?

The process by which cancer cells acquire mutations to adapt to environmental pressures.

Example: Stage a = tumour with A+B mutations; Stage b = subclones with C mutations; Stage c = tumour with A+B+C+E mutations.

What is the normal function of p53 in the cell cycle + example ?

Tumour suppressor gene protects DNA integrity by regulating cell cycle arrest, DNA repair, apoptosis, and senescence

Example: after sun damage → p53 triggers apoptosis or repair to prevent malignant growth.

What happens when p53 is mutated?

Mutant p53 loses tumour-suppressor function -> genomic instability -> stress regulation changes (oxidative + DNA damage) and increased mutation accumulation → cancer progression.

What are DNA repair mechanisms in cancer prevention?

Cell cycle checkpoints (G1/G2) incorporate repair processes. Example: mismatch repair (MMR) corrects replication errors (mismatch, idels)

What happens in deficiency of mismatch repair (dMMR) enzymes?

Mutations in MLH1, PMS2, MSH2, MSH6 enzymes -> MSI. MSI-high tumours cannot repair DNA mutations, -> immunogenic tumours that can be targeted with immunotherapy.

What are the hallmarks of cancer?

Evading growth suppressors

Avoiding immune destruction

Enabling replicative immortality

Activating invasion/metastasis

Deregulating metabolism

Uncontrolled proliferation.

What are umbrella and basket trial designs in cancer research?

Umbrella: multiple targeted therapies in one cancer type with different mutations

Basket: test one targeted therapy across multiple cancer types sharing the same mutation.

Which breast cancer mutation is targeted by trastuzumab?

HER2 activating -> proliferation.

Which breast cancer mutation is targeted by CDK inhibitors?

CCDN1 activating ->proliferation -> Tx CDK4/6 inhibitors.

Which breast cancer mutation is targeted by MAPK inhibitors?

MAPK inactivating -> apoptosis

Which breast cancer mutations currently have no targeted drugs?

PI3KCA (activating) TP53 (inactivating)

How can pharmacists critically analyse cancer genetic research?

Evaluate trial design (umbrella/basket),

molecular targets

evidence strength

clinical relevance

patient care