Cancer Biology: Development, Genetics, and Treatment Strategies

What is cancer?

Uncontrolled growth of abnormal cells. 

List the stages of cancer development.

Mutation → hyperplasia → dysplasia → in situ cancer → invasive cancer.

What does intra-tumour heterogeneity mean?

Different populations of cells exist within a tumour (e.g., luminal vs basal).

What does inter-tumour heterogeneity mean?

A tumour has mostly basal-like or mostly luminal-like cells, but not fully one type.

Is cancer a genetic disease?

it has genetic origin, due to DNA mutations, but is influenced by extrinsic factors too.

Name two extrinsic factors influencing cancer growth.

Soluble factors (growth factors), extracellular matrix, immune interactions, environment.

What are tumour suppressor genes and oncogenes responsible for?

They help control normal cell growth.

In pancreatic cancer progression, what mutates first: oncogenes or tumour suppressor genes?

Oncogenes mutate first, followed by tumour suppressor genes.

What is angiogenesis?

Formation of blood supply by cancer cells.

How do cancer cells metastasize?

Detach, travel via vascular/lymphatic system, and grow in secondary sites.
detachement->intravasation->travel-> extravasation-> micrometastsis->macrometastasis

List intrinsic factors promoting cancer.

Mutated tumour suppressor/oncogene, deregulated cell cycle, dysregulated signalling, chromosomal instability.

Give examples of extrinsic factors promoting cancer.

Growth factors, immune cells (macrophages), hypoxia/pH, extracellular matrix remodeling.

Name four cancer treatments.

Surgery, chemotherapy, radiation, immunotherapy.

What protein is targeted by immunotherapy to circumvent immune evasion?

PD-1 protein.

Give one example of a targeted therapy for HER2-positive breast cancer.

Herceptin (monoclonal antibody).

Give one example of a targeted therapy for EGFR lung cancer.

Iressa (small molecule EGFR inhibitor).

Evidence that cancer is a genetic disease (name two points).

Carcinogens are mutagens, incidence increases with age, inherited predisposition, chromosomal instability, DNA repair defects.

What are the main types of mutations in cancer?

Substitutions, insertions, deletions, duplications, inversions, translocations.

What chromosomal abnormality is associated with CML/AML?

Philadelphia chromosome: BCR-ABL gene fusion.

What percentage of cancers are inherited?

5-10%.

Germline mutations: inherited or acquired?

Inherited.

Somatic mutations: inherited or acquired?

Acquired.

What causes somatic mutations?

Tobacco, UV radiation, aging.

Define oncogene.

Mutated form of a gene promoting cell growth; gain of function; dominant. 

Define tumour suppressor gene.

Healthy gene preventing abnormal growth; mutations cause loss of function; recessive.

Examples of tumour suppressor gene syndromes.

Retinoblastoma (RB1), FAP (APC), Li-Fraumeni (TP53).

Examples of oncogene-linked familial cancers.

MEN2 (RET), HPRCC (MET).

Mechanisms of oncogene activation.

Amplification, translocation, point mutations.

Example of oncogene mutation in bladder carcinoma.

H-ras activation by G→T missense mutation (gly→val).

Mutation distribution in oncogenes vs tumour suppressors.

Oncogenes: few domains, usually missense mutations. Tumour suppressors: widespread, missense and premature termination.

What are the three functional classes of cancer-related genes?

Gatekeepers, caretakers, landscapers.

Give an example of a gatekeeper gene.

RB1 (tumour suppressor), RET (oncogene).

Give an example of a caretaker gene.

BRCA1, BRCA2 (DNA repair genes).

Give an example of a landscaper gene.

Extracellular matrix genes.

What is the function of DNA repair genes?

Maintain genome integrity; loss increases mutation accumulation.

What hypothesis explains retinoblastoma inheritance?

Two-hit hypothesis (Knudson's).

What gene is mutated in retinoblastoma?

RB1 on chromosome 13.

Sporadic vs inherited retinoblastoma: which is usually bilateral?

Inherited (bilateral, ~80%).

Sporadic vs inherited retinoblastoma: which has family history?

Inherited.

What is loss of heterozygosity?

Loss of the remaining normal allele, leading to cancer.

What does haploinsufficiency mean?

One allele loss is enough to cause cancer.

Give an example of a haploinsufficient tumour suppressor gene.

PTEN or NF1.

What is the role of p53?

Induces cell-cycle arrest or apoptosis after DNA damage.

Why can mutant p53 cancel out normal allele effects?

Forms tetramers with mutant subunits, most complexes lose function.

What is the multistep model of cancer?

Cancer develops through multiple mutations over decades.

What factor strongly increases cancer incidence with age?

Accumulation of mutations over time.

How many mutations are typically required for sporadic colorectal cancer?

Around 5 critical gene mutations.

What gene often mutates first in colorectal cancer progression?

APC (tumour suppressor).

What percentage of adenomas become cancerous?

~10%.

How long can it take for an adenoma to progress to cancer?

10+ years.

Explain the process of cancer progression from a single mutation to invasive cancer.

Mutation → hyperplasia → dysplasia → in situ cancer → invasive cancer.

Describe how intra-tumour and inter-tumour heterogeneity affect cancer treatment outcomes.

Intra-tumour heterogeneity = different cell populations within the tumour, some may resist treatment and repopulate. Inter-tumour heterogeneity = tumours dominated by one subtype (basal or luminal), but not purely one. This diversity makes treatment less uniformly effective.

Explain how cancer cells metastasize from the primary tumour to secondary sites.

They induce angiogenesis to form blood supply, detach due to molecular changes, travel via vascular/lymphatic systems, and colonize distant tissues forming secondary tumours.

Describe the differences between germline and somatic mutations in cancer.

Germline: inherited, present in every cell, less common, passed to offspring. Somatic: acquired, not inherited, caused by environmental factors like UV/tobacco/aging, most common form.

Explain Knudson's two-hit hypothesis in the context of retinoblastoma.

Inherited: child already has one defective RB1 allele (first hit), second somatic mutation (second hit) triggers disease → often bilateral and early onset. Sporadic: both hits occur somatically, later onset, usually unilateral.

Describe how mutations in DNA repair genes (caretakers) contribute indirectly to cancer development.

Loss-of-function mutations prevent repair of DNA damage, leading to accumulation of mutations in tumour suppressor genes or proto-oncogenes, increasing cancer likelihood.

Explain why p53 mutations are especially damaging compared to loss of other tumour suppressors.

P53 functions as a tetramer; mutant subunits disrupt the entire complex, meaning even one defective allele can abolish function. This dominant-negative effect allows cancer cells to bypass DNA repair/apoptosis.

Describe the multistep model of colorectal cancer development.

Normal epithelium → APC mutation → adenoma formation → accumulation of mutations (tumour suppressors & oncogenes) → chromosomal instability → carcinoma. Takes ~10+ years, with ~10% of adenomas progressing to cancer.

What does spectral karyotyping identify?

Chromosomes by using special fluorescent dyes; chromosomes 1-23 dyed in different colours.

Chromosomes by using special fluorescent dyes; chromosomes 1-23 dyed in different colours.

What does spectral karyotyping identify?

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