cancers as evolving populations

Why is cancer considered a genetic disease?

Cancer results from genetic mutations and/or epigenetic alterations that disrupt normal cellular regulation.

What are the two major molecular causes of cancer?

Genetic mutations and epigenetic alterations.

What is a genetic mutation?

A permanent change in the DNA sequence.

What is an epigenetic change?

A heritable change in gene expression without alteration of the DNA sequence.

How can environmental mutagens contribute to cancer?

They damage DNA, increasing the likelihood of cancer-causing mutations.

How do X-rays and gamma rays promote carcinogenesis?

They induce DNA double-strand breaks.

How does UV radiation promote cancer?

It causes DNA damage that can lead to mutations.

How does cigarette smoke promote cancer?

It contains mutagens that cause DNA sequence alterations.

How do reactive oxygen species (ROS) contribute to cancer?

They cause oxidative DNA damage.

How can viruses cause cancer?

By introducing oncogenic genetic material or disrupting normal cellular genes.

What is insertional mutagenesis?

Integration of viral DNA into the host genome, disrupting gene regulation.

What proportion of cancers are associated with inherited predisposition variants?

Approximately 5–10%.

What is a cancer predisposition gene?

A gene variant that increases an individual's lifetime risk of developing cancer.

What is the RB1 gene?

A tumour suppressor gene associated with retinoblastoma syndrome.

What syndrome results from inherited RB1 mutations?

Retinoblastoma syndrome.

What is TP53?

A tumour suppressor gene that regulates DNA damage responses and cell-cycle control.

What syndrome is associated with inherited TP53 mutations?

Li-Fraumeni syndrome.

Which cancers are commonly associated with Li-Fraumeni syndrome?

Sarcomas, lymphomas, gliomas, and breast cancer.

Why do DNA repair defects increase cancer risk?

Mutations accumulate because damaged DNA is not repaired effectively.

What is the normal role of DNA repair systems?

To maintain genomic stability by correcting DNA damage.

What is mismatch repair (MMR)?

A DNA repair pathway that corrects replication errors.

Which cancers are associated with mismatch repair defects?

Colon, stomach, and uterine cancers.

Why do highly mitotic tissues have increased cancer risk?

More cell divisions increase opportunities for replication errors and mutations.

Why does chronic inflammation increase cancer risk?

It increases cell turnover and mutation accumulation.

How can inflammatory bowel disease promote cancer?

Chronic inflammation increases epithelial turnover and mutation frequency.

How can NASH increase cancer risk?

Persistent liver injury increases regeneration and mutation accumulation.

What is aneuploidy?

An abnormal number of chromosomes.

How can aneuploidy contribute to cancer?

It disrupts gene dosage and genomic stability.

What is copy number loss?

Loss of chromosomal regions containing important genes.

Why is loss of RB1 or TP53 significant?

It removes critical tumour suppressor functions.

How can epigenetic alterations cause cancer?

By changing gene expression patterns without altering DNA sequence.

Can epigenetic changes be inherited during cell division?

Yes, they can be passed from parent cells to daughter cells.

Can cancer occur with relatively few mutations?

Yes, if significant epigenetic dysregulation is present.

What is a clone?

A population of cells descended from a single progenitor cell.

What does monoclonal mean?

Derived from a single ancestral cell.

What does polyclonal mean?

Derived from multiple ancestral cells.

Are most cancers monoclonal or polyclonal?

Monoclonal.

What is a clonal mutation?

A mutation present in all tumour cells.

What is a subclonal mutation?

A mutation present in only a subset of tumour cells.

Why are clonal mutations found in every tumour cell?

They occurred early in tumour development before expansion of the clone.

Why are subclonal mutations found in only some tumour cells?

They arose later during tumour evolution.

What evidence suggests most cancers are monoclonal?

X chromosome inactivation, antigen receptor gene rearrangement, and mitochondrial mutations.

How does X chromosome inactivation provide evidence for clonality?

All tumour cells have the same X chromosome inactivated, indicating origin from one cell.

What is random X chromosome inactivation?

Early developmental silencing of either the maternal or paternal X chromosome.

What pattern of X chromosome inactivation is expected in normal tissue?

A mixture of maternal and paternal X chromosome inactivation.

What pattern of X chromosome inactivation is expected in a monoclonal tumour?

The same X chromosome is inactivated in all tumour cells.

How does antigen receptor gene recombination demonstrate clonality?

All malignant lymphocytes share the same rearranged receptor sequence.

What is VDJ recombination?

Genetic rearrangement that generates diverse B-cell and T-cell receptors.

Why is healthy lymphoid tissue polyclonal?

Many lymphocyte clones possess different receptor rearrangements.

What PCR finding suggests lymphoma?

A single dominant antigen receptor rearrangement.

How can mitochondrial mutations demonstrate clonality?

The same mitochondrial mutation is present in all tumour cells.

Why are viral integration sites evidence for clonality?

All tumour cells contain the viral DNA inserted at the same genomic location.

What is a founder mutation?

An early mutation present in every descendant tumour cell.

What is a driver mutation?

A mutation that confers a selective growth or survival advantage.

What is a passenger mutation?

A mutation that does not affect cellular fitness.

How do driver mutations contribute to cancer evolution?

They promote expansion of clones with increased fitness.

How do passenger mutations arise?

As by-products of ongoing mutation accumulation.

Do passenger mutations provide a growth advantage?

No.

What is tumour evolution?

The ongoing genetic diversification and selection of cancer cell populations.

Why are cancers considered evolving populations?

Mutations continuously arise and alter the fitness of tumour cells.

What is Darwinian evolution in cancer?

Selection of clones with advantageous mutations.

What is natural selection in tumour biology?

Fitter cancer cells preferentially survive and proliferate.

How can chemotherapy act as a selective pressure?

It eliminates sensitive cells while resistant clones survive.

Why does treatment resistance emerge?

Resistant subclones gain a survival advantage under therapy.

What is neutral evolution in cancer?

Accumulation of mutations that do not affect fitness.

What is random drift?

Random persistence or loss of neutral mutations.

How do passenger mutations spread through tumours?

Through random drift rather than selection.

What is intratumour heterogeneity?

Genetic and epigenetic diversity within a tumour.

Why is intratumour heterogeneity clinically important?

Different tumour cells may respond differently to treatment.

What is spatial heterogeneity?

Genetic differences between regions of the same tumour.

What is temporal heterogeneity?

Genetic differences that arise as a tumour evolves over time.

Why might one biopsy not represent the entire tumour?

Different tumour regions may contain different subclones.

How does temporal heterogeneity affect treatment?

The tumour may evolve resistance during therapy.

What is a phylogenetic tree in cancer biology?

A model showing evolutionary relationships between tumour subclones.

What does the trunk of a tumour phylogenetic tree represent?

Clonal founder mutations shared by all tumour cells.

What mutations are found in the trunk?

Driver mutations and other early clonal alterations.

What do branches represent in a tumour phylogenetic tree?

Subclonal mutations shared by subsets of tumour cells.

What do twigs or leaves represent?

Recent private mutations found in small populations.

Why are trunk mutations attractive therapeutic targets?

They are present in every tumour cell.

What is clonal succession?

The historical concept that progressively more aggressive clones replace earlier clones.

Who proposed clonal succession theory?

Nowell in 1976.

What replaced clonal succession theory?

The modern tumour evolution model.

What is the major advantage of tissue biopsy?

Direct analysis of tumour tissue.

What is a disadvantage of tissue biopsy?

It is invasive and subject to sampling bias.

What is sampling bias in cancer diagnosis?

A biopsy may not capture the full genetic diversity of the tumour.

What is the advantage of autopsy studies?

They allow comprehensive analysis of all tumour sites.

Why are autopsy studies limited clinically?

They occur only at the end of life.

What is a liquid biopsy?

Analysis of tumour-derived material in body fluids.

What is ctDNA?

Circulating tumour DNA released into biofluids by cancer cells.

Which biofluids can contain ctDNA?

Blood, urine, cerebrospinal fluid, and ascitic fluid.

What is the major advantage of liquid biopsy?

It can monitor tumour evolution non-invasively.

How can liquid biopsy assess tumour burden?

By measuring levels of tumour-specific mutations in ctDNA.

How can liquid biopsy guide targeted therapy?

By identifying actionable driver mutations.

How can liquid biopsy detect resistance?

By identifying emerging resistance mutations before clinical progression.

Why can ctDNA detect relapse earlier than imaging?

Genetic changes can be detected before visible tumour growth occurs.

What is an EGFR-sensitive mutation?

A mutation that makes tumour cells susceptible to EGFR-targeted therapy.

How does resistance emerge during EGFR therapy?

A resistant subclone survives and expands under treatment pressure.

Why does a second resistance mutation sometimes appear?

Ongoing tumour evolution generates additional resistant clones.

How does tumour evolution explain treatment failure?

Selective pressures favour resistant populations that eventually dominate.

What is the relationship between mutation and selection in cancer?

Mutations generate diversity while selection determines which clones expand.